(Hypertension. 1998;31:657-664.)
© 1998 American Heart Association, Inc.
Renal Changes Induced by Nitric Oxide and Prostaglandin Synthesis Reduction
Effects of Trandolapril and Verapamil
Maria T. Llinás;
Juan D. González;
Francisca Rodríguez;
Eduardo Nava;
Stefano Taddei;
; F. Javier Salazar
From I Clinica Medica, University of Pisa, Pisa, Italy (S.T.); and
Departamento de Fisiología, Facultad de Medicina (M.T.L., J.D.G., F.R.,
E.N., F.J.S.), Murcia, Spain.
Correspondence to F. Javier Salazar, Departamento de Fisiología, Facultad de Medicina, 30100 Murcia, Spain. E-mail salazar{at}fcu.um.es
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Abstract
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Abstract—The benefits of the
simultaneous administration of low doses of a calcium
antagonist and a converting enzyme inhibitor in
the treatment of hypertension and renal vasoconstriction are well
established. The objective of this study was to evaluate whether the
administration of low doses of a calcium antagonist and a
converting-enzyme inhibitor have beneficial effects in
treating the renal alterations induced by the acute administration of a
cyclooxygenase inhibitor when nitric
oxide synthesis is reduced. These effects were examined in
anesthetized dogs before and during an acute sodium load. It
was found that the intrarenal infusion of meclofenamate (5 µg
· kg-1 · min-1),
simultaneously with a low dose of
NG-nitro-L-arginine methyl ester
(1 µg · kg-1 · min-1),
produced a 40% decrease of renal blood flow and glomerular
filtration rate and a reduction in the renal excretory response to the
sodium load. In a second group of dogs, intrarenal
verapamil (0.5 µg · kg-1 ·
min-1) was effective in blocking the effects of nitric
oxide and prostaglandin synthesis inhibition on sodium
excretion and glomerular filtration rate but did not modify
the effects on renal blood flow. An intrarenal infusion of trandolapril
(0.3 µg · kg-1 · min-1) was
effective in a third group of dogs in reducing the renal
hemodynamic effects but not in preventing the
antinatriuretic effect observed in the first group.
Finally, in a fourth group, the simultaneous administration
of verapamil and trandolapril was effective in treating all
the renal changes induced by the cyclooxygenase
inhibitor when nitric oxide synthesis was reduced. These
results suggest that the combination of low doses of trandolapril and
verapamil has additive effects in treating the renal
vasoconstriction and antinatriuresis induced by the acute
administration of a cyclooxygenase
inhibitor, when nitric oxide synthesis is reduced.
Key Words: vasoconstriction • nitric oxide • prostaglandin • sodium sensitivity • calcium antagonists converting enzyme inhibitors
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Introduction
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The role of NO in
mediating the renal response to short- and long-term increments in
sodium intake is supported by studies showing that a decrease in NO
synthesis reduces the renal ability to eliminate a sodium load and
induces the development of sodium-sensitive
hypertension.1 2 3 4 5 On the other hand, it has been
suggested that there is an important interaction between NO and PG in
the regulation of the renal hemodynamic and excretory
function.2 3 The existence of this interaction is
supported by the results obtained in acute studies showing that
meclofenamate administration produces renal vasoconstriction and
reduces the excretory response to an acute sodium load when NO
synthesis is reduced.2 3 These results support
the hypothesis that the intake of cyclooxygenase
inhibitors can induce the development of hypertension and
important changes in renal function in situations where NO synthesis is
partially decreased. In support of this hypothesis, it has been
reported that NO synthesis seems to be reduced in salt-sensitive
hypertension6 and that the administration of a
cyclooxygenase inhibitor induces an
increase of arterial pressure in salt-sensitive
hypertensive patients.7
Recent studies of our group have demonstrated that captopril (0.8
µg · kg-1 ·
min-1) is only effective in treating the renal
vasoconstriction,3 and verapamil (2
µg · kg-1 ·
min-1) is effective in treating the
antinatriuretic effects8
induced by acute meclofenamate administration, when NO is reduced.
Based on these findings and on the well-known pharmacological actions
of calcium antagonists and CEIs,9 10 11
it could be expected that the combination of the two drugs would be
effective in treating both renal effects produced by the acute
inhibition of PG synthesis when NO production is reduced.
Several studies have suggested that CEIs and calcium
antagonists have additive and synergistic effects on sodium
balance, on the renin-angiotensin
system,9 and in
hypertension.10 11 The objective of the
present study was to determine the effects of low doses of a CEI
(trandolapril, 0.3 µg · kg-1 ·
min-1) and/or a calcium antagonist
(verapamil, 0.5 µg ·
kg-1 · min-1) in
blocking the renal vasoconstriction and
antinatriuretic effects induced by the acute
administration of a cyclooxygenase
inhibitor when NO synthesis is partially reduced. These
effects were evaluated in anesthetized dogs before and during
an acute sodium load to examine whether simultaneous
treatment with low doses of both drugs also improves the renal ability
to eliminate an acute sodium load.
The results obtained may have some important clinical implications
because of the following during aging: 1) there is an
endothelial dysfunction,6 2) the
intake of anti-inflammatory drugs is enhanced,1
and 3) the sodium sensitivity of blood pressure is
increased.13 That acute sodium load can be used
for the assessment of salt responsiveness of blood pressure has been
demonstrated by Weinberger et al.14 The possible
efficacy of combining low doses of these drugs in treating the renal
effects induced by the acute administration of a
cyclooxygenase inhibitor, when NO
synthesis is reduced, may also have therapeutic importance since the
incidence of side effects is
dose-dependent.10 15
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Methods
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Surgical Preparation
Experiments were accomplished in mongrel dogs of either sex (15
to 24 kg) anesthetized with sodium pentobarbital and were
designed according to Guiding Principles in the Care and Use of
Laboratory Animals approved by the Council of the American
Physiological Society. Catheters were placed in the
femoral artery for measurement of MAP and in the femoral vein for
infusion of inulin and additional anesthetic (0.6 mL/min). Inulin was
dissolved in isotonic saline and infused to achieve plasma fructose
levels of 1.7 mmol/L. Both kidneys were exposed through flank
incisions and the ureters cannulated to allow for comparison of the
renal function of both kidneys. The dogs were placed in a metal frame
that mimicked their usual standing position. The renal arteries were
fitted with noncannulating electromagnetic flow probes and connected to
flowmeters. Distal to the flow probe, a curved 23-gauge needle attached
to polyethylene tubing was inserted into the renal arteries and
connected to a peristaltic pump for infusion of saline or drugs (0.6
mL/min). Finally, a 45-minute stabilization period was allowed before
experimental maneuvers were begun.
Experimental Groups
Group 1 (n=6)
After two 15-minute control clearances, L-NAME (1 µg ·
kg-1 · min-1) was
infused into the right renal artery until the end of the experiment.
Fifteen minutes after the initiation of L-NAME infusion, meclofenamate
(5 mg · kg-1 ·
min-1) was administered into both renal arteries
for the duration of the experiment. Thirty minutes after initiating the
meclofenamate infusion, two additional 15-minute clearances were
obtained, and a 5% ECVE with isotonic saline was performed during 45
minutes. Two clearances were obtained: during the last 10 minutes of
saline infusion and 10 minutes after cessation of this infusion.
Finally, 30 minutes after the end of saline infusion, two additional
15-minute clearances were obtained.
Group 2 (n=6)
After two 15-minute control clearances, L-NAME and meclofenamate
were infused into the renal arteries in the same order and time
sequence as in group 1. Thirty minutes after meclofenamate
administration was initiated, two 15-minute clearances were obtained,
and an infusion of verapamil (0.5 µg ·
kg-1 · min-1) into
both renal arteries was begun. Two additional 10-minute clearances were
then collected 30 minutes after the continuous infusion of
verapamil started. Thereafter, the 5% ECVE was carried out
during 45 minutes, and the clearances obtained, during and after the
ECVE, were similar to those mentioned in group 1.
Group 3 (n=6)
The experimental protocol accomplished in this group is similar
to that of group 2, except that trandolapril (0.3 µg ·
kg-1 · min-1) was
administered instead of verapamil. In preliminary
experiments it was found that the dose of trandolapril used is
effective in blocking the decrease in RBF and the increase in MAP
induced by the intrarenal infusion of Ang I during 30 minutes (2
ng · kg-1 ·
min-1).
Group 4 (n=6)
Group 4 received the same treatment as group 2, but both
trandolapril (0.3 µg · kg-1 ·
min-1) and verapamil (0.5 µg
· kg-1 · min-1)
were infused into the renal arteries instead of verapamil
alone. Two 10-minute clearances were collected 30 minutes after the
continuous infusion of verapamil and trandolapril started.
Afterward, the 5% ECVE was carried out with isotonic saline, and
clearances were obtained during the last 10 minutes of saline infusion
and 10 minutes after cessation of the expansion. Finally, 30 minutes
after the end of the ECVE, two more 15-minute clearances were
obtained.
Group 5 (n=4)
After two 15-minute control clearances, trandolapril (0.3
µg · kg-1 ·
min-1) and verapamil (0.5 µg
· kg-1 · min-1)
were infused into both renal arteries until the end of the experiment.
Thirty minutes after the initiation of trandolapril and
verapamil infusion, two additional 10-minute clearances
were obtained, and a 5% ECVE with isotonic saline was performed during
45 minutes. Two clearances were obtained: during the last 10 minutes of
saline infusion and 10 minutes after the end of this infusion. Finally,
30 minutes after the end of saline infusion, two more 15-minute
clearances were obtained.
Analytical Methods
Renal clearances were taken during each experimental period to
determine GFR, UNaV, UKV, and UV. Blood samples for hematocrit and
plasma sodium, potassium, and inulin concentrations were also obtained
during each renal clearance. GFR was measured by the clearance of
inulin. Inulin concentrations were analyzed by the anthrone
method. Concentrations of sodium and potassium were measured by flame
photometry (Corning 435).
Statistical Analysis
The data for the two clearance periods for each condition were
averaged for statistical comparisons because the fluid and solute
excretions were in steady state conditions. There were no differences
between the results obtained during both renal clearances of each
period. Data are expressed as mean±SE. Significance of differences in
values of each period in the same group and kidney was evaluated using
a one-way ANOVA and the Duncan multiple range test. Differences between
the same period of different kidneys and groups were calculated with a
two-way ANOVA and the Duncan test.
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Results
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Group 1
Table 1
and Fig 1 show that the intrarenal administration
of meclofenamate when NO synthesis was reduced in the right kidney,
with a subpressor dose of L-NAME, induced a significant rise of MAP
(P<.05) that was maintained throughout the experiment. The
simultaneous inhibition of NO and PG synthesis in the right
kidney provoked an increase of renal vascular resistance and a decrease
of UNaV, UKV, and UV that was significantly greater (P<.05)
than that induced by the PG synthesis inhibition in the left kidney. It
can be observed (Table 1, Fig 2) that the
simultaneous inhibition of NO and PG synthesis, before the
ECVE, provoked a significant decrease (P<.05) of GFR
(46%), RBF (43%), UNaV (90%), and UV (84%). The PG synthesis
inhibition in the left kidney induced a significant decrease
(P<.05) of RBF (12%), UNaV (60%), and UV (42%).
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Table 1. Effects Induced by Administration of Meclofenamate
(Meclo) into Both Renal Arteries and of L-NAME into Right Renal Artery,
Before and After Inducing an Acute 5% ECVE
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Figure 1. Changes in MAP during the intrarenal infusion of
L-NAME and meclofenamate (MECLO) before and after induction of an acute
5% volume expansion (EXP 5%) in control dogs (Vehicle) and in dogs
treated with verapamil and/or trandolapril.
*P<.05 vs control period.
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Figure 2. Changes in RBF and GFR during the intrarenal
infusion of L-NAME and meclofenamate (MECLO) before and after induction
of an acute 5% volume expansion (EXP 5%) in control dogs (Vehicle)
and in dogs treated with verapamil and/or trandolapril.
*P<.05 vs control period.
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The ECVE induced a significant increase (P<.05) of GFR in
the right kidney to control levels, but RBF remained significantly
decreased (P<.05) (Table 1
, Fig 2). During the ECVE, GFR
was similar in both kidneys, and blood flow was significantly lower
(P<.05) in the right than in the left kidney. Similarly, it
can be observed (Table 1, Fig 3) that the
renal excretory response to the ECVE was significantly lower
(P<.05) in the right kidney (simultaneous
inhibition of NO and PG synthesis) than in the left kidney (inhibition
of PG synthesis). During the postexpansion period, UNaV and UV were
also significantly greater (P<.05) in the left than in the
right kidney.
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Figure 3. Effects of verapamil and/or
trandolapril on the ECVE-induced increases of UNaV during the infusion
of meclofenamate (Meclo) into both renal arteries and L-NAME into the
right renal artery. Top left, Results obtained in control dogs
(Vehicle). Top right, Results obtained in dogs treated with
verapamil. Bottom left, Results obtained in dogs treated
with trandolapril. Bottom right, Results obtained in dogs treated with
verapamil and trandolapril. *P<.05 vs
control period; +P<.05 between both kidneys.
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Group 2
Table 2 and Figs 1, 2, and 3 show
the effects of verapamil during the intrarenal
administration of a cyclooxygenase
inhibitor, when NO was reduced in the right kidney.
Although not shown in Table 2, the administration of L-NAME into the
right renal artery and meclofenamate into both renal arteries induced
an increase in MAP (from 119±6 to 137±6 mm Hg) and changes in
the renal hemodynamic and excretory function that were
similar to those found in group 1. The increase in renal vascular
resistance was significantly greater in the right (NO and PG reduction)
than in the left kidney (PG reduction). It can be observed (Table 2 and
Figs 1 and 2) that MAP remained increased and blood flow decreased in
both kidneys when verapamil was infused into the renal
arteries. Verapamil partially abolished the renal
vasoconstriction induced by the NO and PG synthesis inhibition, since
GFR was similar to that found during the control period. However,
verapamil infusion completely abolished the
antinatriuretic effect induced by the meclofenamate
administration, when intrarenal NO synthesis was reduced, since UNaV
and UV were also similar during the verapamil infusion and
control periods. It also can be observed in Table 2 that the
administration of verapamil into the left kidney induced a
significant increase of UNaV and UV and that RBF, UNaV, and UKV were
greater in the left than in the right kidney before the ECVE.
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Table 2. Effects of Intrarenal Infusion of
Verapamil (0.5
µg · kg-1 · min-1) (Verap) on Renal
Changes Induced by PG Synthesis Inhibition in Both Kidneys With
Meclofenamate (Meclo) and Inhibition of NO Synthesis in Right Kidney
With L-NAME
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During the ECVE, GFR did not change and RBF increased significantly
(P<.05) in both kidneys to levels similar to those found in
the control period (Table 2 and Fig 2). Nevertheless, RBF in the right
kidney was lower than in the left kidney. These results indicate that
the administration of this low dose of verapamil is not
effective in blocking totally the renal vasoconstriction produced by
the administration of a cyclooxygenase
inhibitor, when NO synthesis is reduced. Finally, it can be
observed in Table 2 and Fig 3 that the effect of the
simultaneous reduction in NO and PG synthesis on the renal
excretory response to ECVE was completely prevented by the
administration of the low dose of verapamil. In fact, the
ECVE-induced increases of UNaV and UV were significantly greater
(P<.05) in this group than in the other groups of this
study.
Group 3
Table 3 and Figs 1, 2, and 3 show
the effects of trandolapril during the intrarenal administration of a
cyclooxygenase inhibitor, when NO was
reduced in the right kidney. Although not shown in Table 3, the
administration of L-NAME into the right renal artery and meclofenamate
into both renal arteries induced an increase in MAP (from 127±4 to
139±4 mm Hg) and caused changes in the renal
hemodynamic and excretory function that were similar to
those found in group 1. Again, the changes induced by the
simultaneous decrease in NO and PG synthesis were greater
than those induced by the administration of the PG synthesis
inhibitor. GFR and RBF decreased significantly
(P<.05), to 24±4 and 144±9 mL/min, respectively, in the
right kidney, and to 33±2 (NS) and 167±11 mL/min (P<.05),
respectively, in the left kidney. Table 3 and Fig 1 show that MAP
remained elevated when trandolapril (0.3 µg ·
kg-1 · min-1) was
administered into both renal arteries. However, the administration of
this CEI reduced significantly (P<.05) the renal
vasoconstrictor effect induced by the administration of L-NAME and
meclofenamate, since GFR was similar to that found during the control
period and RBF was only slightly reduced (P<.05). With
respect to the renal excretory function, it was only partially improved
by the trandolapril administration. UNaV, UKV, and UV remained
significantly decreased (P<.05) in the left kidney during
the administration of this CEI (Table 3). On the other hand, the
reduction in Ang II synthesis completely abolished the changes in renal
hemodynamic and excretory function induced by the PG
synthesis inhibition in the left kidney.
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Table 3. Effects of Intrarenal Infusion of Trandolapril (0.3
µg · kg-1 · min-1) (Trand) on Renal
Changes Induced by PG Synthesis Inhibition in Both Kidneys With
Meclofenamate (Meclo) and Inhibition of NO Synthesis in Right Kidney
With L-NAME
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The ECVE provoked a significant increase (P<.05) of blood
flow in the right kidney (Table 3 and Fig 2). Table 3 shows that both
GFR and RBF were similar in both kidneys during the ECVE. However, the
ECVE-induced increases in UNaV, UKV, and UV were greater in the left
than in the right kidney. These results indicate that Ang II synthesis
inhibition does not prevent the altered excretory response to an ECVE,
when NO and PG synthesis are reduced.
Group 4
Table 4 and Figs 1, 2, and 3 show
the effects of verapamil and trandolapril during the
intrarenal administration of a cyclooxygenase
inhibitor, when NO synthesis was reduced in the right
kidney. Although not shown in Table 4, the administration of L-NAME
into the right renal artery and meclofenamate into both renal arteries
induced an increase in MAP (from 125±4 to 142±4 mm Hg) and
caused changes in the renal hemodynamic and excretory
function that were similar to those found in group 1. It can be seen in
Table 4 and Figs 1 and 2 that the increase of MAP and renal
vasoconstriction were completely abolished by the
simultaneous administration of verapamil (0.5
µg · kg-1 ·
min-1) and trandolapril (0.3 µg ·
kg-1 · min-1).
Furthermore, the administration of verapamil and
trandolapril, before the ECVE, provoked a significant increase of UNaV
(P<.05) but no significant changes of UV in either
kidney.
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Table 4. Effects of Intrarenal Infusion of Trandolapril (0.3
µg · kg-1 · min-1) (Trand) and
Verapamil (0.5
µg · kg-1 · min-1) (Verap) on Renal
Changes Induced by PG Synthesis Inhibition in Both Kidneys With
Meclofenamate (Meclo) and NO Synthesis Inhibition in Right Kidney With
L-NAME
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During the ECVE there were no changes in renal
hemodynamics and the increases of UNaV and UV were
similar in both kidneys (Table 4, Fig 3). During the postexpansion
period, UNaV and UV remained similarly significantly elevated
(P<.05) in both kidneys.
Group 5
Table 5 shows that the
simultaneous intrarenal administration of
verapamil and trandolapril into both renal arteries did not
induce changes in MAP or GFR. It can be observed that the increases in
RBF (during the ECVE) and in UNaV (before and during the ECVE) were
similar in both kidneys.
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Table 5. Effects of Intrarenal Infusion of Trandolapril (0.3
µg · kg-1 · min-1) (Trand) and
Verapamil (0.5
µg · kg-1 · min-1) (Verap) Before
and After Induction of Acute 5% ECVE
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Discussion
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The results of this study demonstrate that the
simultaneous administration of low doses of
verapamil and trandolapril has beneficial effects in
treating the hypertension, renal vasoconstriction, and antinatriuresis
induced by the acute intrarenal reduction of PG synthesis, when NO
synthesis is decreased. In previous studies performed by our group, it
was observed that the renal effects induced by NO and PG synthesis
reduction are only partially prevented by the intrarenal administration
of captopril (0.8 µg · kg-1 ·
min-1)3 or
verapamil (2 µg · kg-1
· min-1).8 The
present study extends these observations by showing that the acute
simultaneous intrarenal infusion of lower doses of
verapamil (0.5 µg ·
kg-1 · min-1) and
trandolapril (0.3 µg · kg-1 ·
min-1) are effective in preventing the
hypertension, renal vasoconstriction, and
antinatriuretic effects induced by the intrarenal
administration of a cyclooxygenase
inhibitor when NO synthesis is partially reduced. These
effects of the combined therapy were observed with and without
increases of extracellular volume.
The role of NO and PG in the regulation of the renal
hemodynamic and excretory function has been examined
previously1 2 3 8 by the intrarenal infusion of
L-NAME or meclofenamate at doses similar to those used in the
present study. These doses are effective in reducing NO and PG
synthesis.1 2 3 8 We believe that the dose of
L-NAME used does not completely inhibit the intrarenal NO synthesis
because the administration of greater doses produces a significant
renal vasoconstriction.16 17 Trandolapril and
verapamil were intrarenally infused in the present
study because the objective was to evaluate the effects of these drugs
in reducing the renal changes induced by the acute administration of a
cyclooxygenase inhibitor, when NO
synthesis is decreased. The interpretation of the results obtained
would be more difficult if these drugs were infused
intravenously because of the changes in
arterial pressure.
The existence of an important interaction between NO and PG in the
regulation of renal function has been suggested by the results obtained
previously by our group.2 3 8 It was demonstrated
that the administration of a cyclooxygenase
inhibitor elicits a rise of arterial pressure
and an alteration of the renal hemodynamic and
excretory function when NO synthesis is partially reduced. These
results are similar to those found in the present study. The renal
vasoconstriction seems to be secondary to the endogenous
Ang II levels, since this effect was significantly reduced by the
intrarenal infusion of trandolapril (0.3 µg ·
kg-1 · min-1).
Furthermore, in a previous study3 it was found
that a greater dose of captopril (0.8 µg ·
kg-1 · min-1)
completely inhibits the hypertension and renal vasoconstriction induced
by the NO and PG synthesis reductions. However, the
antinatriuretic effect is probably independent of
the Ang II levels because this effect is not reduced by the
administration of these CEIs. The decrease of sodium excretion could be
secondary to an elevation of sodium reabsorption in the
proximal2 8 and distal18 19
tubules and/or to a decrease of renal interstitial
hydrostatic pressure and medullary blood
flow.20 21 22 23
The administration of verapamil (0.5 µg ·
kg-1 · min-1) only
reduced partially the renal vasoconstriction induced by the
cyclooxygenase inhibitor when NO
synthesis was partially inhibited. These effects are similar to those
found in a previous study,8 where a greater dose
of verapamil was used (2 µg ·
kg-1 · min-1),
with the only difference being that the natriuretic effect
of this dose was greater than that found in the present study. When
one takes into account the results obtained with trandolapril and
captopril,3 it can be suggested that
verapamil inhibits the vasoconstrictor effect of Ang II on
the afferent arteriole and that it only reduced partially this effect
on the efferent arteriole. Indeed, GFR increased to control levels and
RBF remained decreased with verapamil when NO and PG
synthesis were reduced. This interpretation of our data is supported by
the results obtained by Carmines et al.24 These
authors observed that the vasoconstrictor effects of Ang II on the
afferent but not on the efferent arteriole were blocked with the
administration of a calcium antagonist.
The infusion of verapamil not only inhibited the
antinatriuretic effect produced by the NO and PG
synthesis reduction but also increased the excretory response to the
ECVE. This natriuretic response to the ECVE could be
secondary to the greater arterial pressure, since it is
known that calcium antagonists increase the
natriuretic response to elevations of arterial
pressure.25 The increases of sodium and water
excretion can be considered paradoxical if one considers that RBF was
reduced. Nevertheless, previous studies have demonstrated that the
natriuresis induced by calcium antagonists is independent
of their hemodynamic actions.25
The natriuretic response to ECVE during the
verapamil administration is similar to that found in a
previous study where a greater dose of verapamil was
administered8 and support the hypothesis that
this calcium antagonist inhibits the increased sodium
reabsorption induced by the NO and PG synthesis reductions. The results
obtained do not indicate the mechanism by which verapamil
inhibits the increased sodium reabsorption, but this effect could occur
in proximal and distal tubules. It has been suggested that
verapamil prevents the effect of the NO and PG synthesis
inhibitors on the proximal tubule by blocking the
antinatriuretic actions of Ang II in this tubular
segment.8 On the other hand, it has been reported
that NO and PG regulate sodium reabsorption in the collecting
tubule18 19 23 and that calcium
antagonists reduce sodium reabsorption in the same tubular
segment.25 26 The natriuresis induced by
verapamil can be due also to an increase in medullary blood
flow, since it is known that calcium antagonists provoke an
increase in medullary blood flow in salt-sensitive hypertensive
animals,25 27 in whom NO production seems
to be reduced.6
The most important finding of this study is that low doses of
trandolapril (0.3 µg · kg-1 ·
min-1) and verapamil (0.5 µg
· kg-1 · min-1)
are more effective when administered simultaneously in the
treatment of the hypertension, renal vasoconstriction, and
antinatriuresis induced by the NO and PG synthesis reductions. The
effects induced by the simultaneous administration of these
doses of verapamil and trandolapril are greater than those
observed during the administration of greater doses of captopril (0.8
µg · kg-1 ·
min-1)3 or
verapamil (2 µg · kg-1
· min-1).8 Therefore,
the results obtained in this study suggest that a combination of low
doses of trandolapril and verapamil is likely to be
beneficial in the treatment of the hypertension, salt sensitivity, and
renal vasoconstriction that could be induced by the intake of a
cyclooxygenase inhibitor in those
patients in whom the NO production is partially reduced. It has
been suggested that during aging sodium-sensitivity of
arterial pressure increases13 and
that there is an endothelial
dysfunction.6 It is also known that the intake of
anti-inflammatory drugs is higher during aging.12
Previous studies have reported that low doses of a calcium
antagonist and a CEI have additive and synergistic effects
in the decrease in arterial pressure when administered to
normotensive or hypertensive patients.9 10 11 28 29
The synergistic effects in the treatment of hypertension during aging
have been demonstrated in one study,11 in which
it was observed that the combination of 5 mg felodipine and 5 mg
enalapril is more effective in reducing arterial pressure
than the administration of a higher dose (10 mg) of felodipine or
enalapril alone. However, the effects of both drugs on renal function
were not evaluated in the study performed by Morgan and
Anderson.11
In summary, the results of this study provide new evidence that a
combination of low doses of a calcium antagonist and a CEI
improves the efficacy in reducing the renal effects induced by the
acute administration of a cyclooxygenase
inhibitor when NO synthesis is partially reduced. When the
results obtained in previous studies of our group are
considered,3 8 the results of this study suggest
that low-dose dual therapy with a calcium antagonist and a
CEI may be better than high-dose monotherapy with one of these drugs in
the treatment of the renal effects produced by a
cyclooxygenase inhibitor when NO
synthesis is reduced.
|
Selected Abbreviations and Acronyms
|
|---|
| Ang I, II |
= |
angiotensin I, II |
| CEI |
= |
converting-enzyme inhibitor |
| ECVE |
= |
extracellular volume expansion |
| GFR |
= |
glomerular filtration rate |
| L-NAME |
= |
NG-nitro-L-arginine
methyl ester |
| MAP |
= |
mean arterial pressure |
| NO |
= |
nitric oxide |
| PG |
= |
prostaglandin |
| RBF |
= |
renal blood flow |
| UKV |
= |
urinary potassium excretion |
| UNaV |
= |
urinary sodium excretion |
| UV |
= |
urine flow rate |
|
|
Acknowledgments
|
|---|
This study was supported by grants from the Fondo de
Investigaciones Sanitarias (FIS, 94/780) of Spain, the European
Community (ERBCHRXCT940645), and Knoll Laboratories (Spain). The
authors acknowledge the generous donations of meclofenamate by
Parke-Davis (Warner-Lambert) and of verapamil and trandolapril by Knoll
Laboratories (Spain).
Received August 22, 1997;
first decision September 25, 1997;
accepted October 1, 1997.
|
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Abstract
Introduction
