Effects of acetaminophen and ibuprofen on renal function
in anesthetized normal and sodium-depleted dogs
ADRIA E. COLLETTI, HELEN W. VOGL, THERESE RAHE, AND EDWARD J. ZAMBRASKI
Department of Cell Biology and Neuroscience, Rutgers,
State University of New Jersey, Piscataway, New Jersey 08854
prostaglandins; glomerular filtration rate; renal blood flow;
sodium depletion
drug that is believed to be a very weak inhibitor of PG
synthesis (27). Thus Acet, in contrast to Ibu, would not
be predicted to have a deleterious effect on the kidney
in a renal PG-dependent state. Acet has no effect on
GFR in normal subjects (2). Acet is also the recommended analgesic for subjects with renal dysfunction
(11).
There are, however, isolated medical case reports of
renal vasoconstriction and acute renal failure resulting
from therapeutic Acet use (3, 6, 12). There are also
reports suggesting that Acet may reduce PGE2 excretion, especially in patients with chronic renal insufficiency (1). We have been unable to find reports that
have evaluated the effects of Acet on kidney function in
a renal PG-dependent state, nor, under these conditions, have the effects of Acet on renal PG synthesis
been quantified.
The purpose of this study was to determine whether
Acet altered renal function in a renal PG-dependent
state. A combination of the stress of anesthesia and the
low-dietary-sodium dog model described by Blasingham and Nasjletti (4) was used as a model of a renal
PG-dependent state. Changes in renal function, as well
as changes in PGE2 synthesis with Acet administration, were evaluated. Comparisons were made with the
known PGE2-synthesis inhibitor Ibu.
METHODS
(PGs) are vasodilators that play
an important role in the preservation of kidney function when activity of the renin-angiotensin system or
the renal sympathetic nerves are elevated. They act to
maintain glomerular filtration rate (GFR) and renal
blood flow (RBF) by modulating the effects of vasoconstrictors such as ANG II or norepinephrine on the renal
vasculature (9). Such conditions would exist during
hypotension, dehydration, or sodium depletion (13), as
well as in disease states such as cirrhosis (32), lupus
(20), and chronic renal failure (8). These are often
referred to as ‘‘renal PG-dependent’’ states.
Aspirin and nonsteroidal anti-inflammatory drugs,
such as ibuprofen (Ibu) and indomethacin, have been
shown to significantly reduce PGE2 synthesis and
consequently adversely alter kidney function (i.e., renal vasoconstriction, sodium retention) in both humans
(2, 14, 17, 32) and animals (28–30) in renal PGdependent states. Acetaminophen (Acet) is an analgesic
RENAL PROSTAGLANDINS
The costs of publication of this article were defrayed in part by the
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solely to indicate this fact.
592
Animals. All animal procedures were approved by the
Rutgers Institutional Animal Care and Use Committee.
Thirty-two adult beagles (10.8 6 1.6 kg) were used for these
studies. Twenty animals were fed a daily ration of 450 g of
Purina dog chow containing 4 g sodium/kg. Twelve dogs were
fed 400 g of a low-sodium diet (0.3 g sodium/kg; Research
Diets, New Brunswick, NJ) for 7 days before surgery. In
addition, on the first day of the low-sodium diet, animals on
this diet received an intramuscular injection of Lasix (100 mg
furosemide; Hoechst Roussel Agri-Vet, Somerville, NJ). This
procedure was used originally to develop one of the first
models of a renal PG-dependent state (4). Water was provided
ad libitum. The animals were fasted for 20–24 h before
surgery.
Surgical procedures. The dogs were anesthetized with
pentobarbital sodium (30 mg/kg iv). The trachea was intubated, and the animal was ventilated with room air. Polyethylene cannulas were inserted into both jugular veins and into
the abdominal aorta inferior to the origin of the renal
arteries. One jugular catheter was used to administer a
priming dose of inulin and p-aminohippuric acid (PAH) in
0.9% NaCl; sustaining solutions of inulin and PAH in saline
were infused at a rate of 1 ml/min. The second jugular
catheter was used to administer Acet or Ibu solutions. The
arterial catheter was connected to a Statham pressure transducer to monitor mean arterial pressure (MAP). Heart rate
(HR) was determined from pulsatile blood pressure (BP). The
8750-7587/99 $5.00 Copyright r 1999 the American Physiological Society
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Colletti, Adria E., Helen W. Vogl, Therese Rahe, and
Edward J. Zambraski. Effects of acetaminophen and ibuprofen on renal function in anesthetized normal and sodiumdepleted dogs. J. Appl. Physiol. 86(2): 592–597, 1999.—In
certain conditions, renal prostaglandins (PGs) are important
determinants of kidney function. Under these ‘‘renal PGdependent states,’’ pharmacological inhibition of vasodilatory
PG may result in excessive renal vasoconstriction and adversely affect kidney function. The purposes of this study
were to determine whether acetaminophen (Acet), a weak
PG-synthesis inhibitor, influences kidney function in the
renal PG-dependent state of anesthesia and sodium depletion. Comparisons were made with ibuprofen (Ibu). Measurements of PGE2 excretion were used to assess renal PG
synthesis. Acet (15 mg/kg) and Ibu (10 mg/kg) both decreased
renal blood flow and glomerular filtration rate by ,20–30% in
normal, anesthetized, sodium-replete dogs. Although Acet
produced similar changes in renal blood flow and glomerular
filtration rate in the low-sodium dogs, Ibu caused a significantly greater renal vasoconstriction (64 6 10%) in these
animals. Both Acet and Ibu inhibited urinary PGE2 excretion
in sodium-replete and low-sodium dogs. Ibu tended to have a
greater and more prolonged effect than did Acet. These
results suggest that Acet alters PGE2 excretion and kidney
function under renal PG-dependent conditions; the effects,
however, are less severe than those seen with Ibu.
593
ACETAMINOPHEN AND RENAL FUNCTION
RESULTS
Effects of a low-sodium diet. Across all groups, comparisons were made between normal and low-sodium
animals. Control values for hemodynamic and renal
function parameters are shown in Table 1. The two
groups matched closely with similar values for renal
hemodynamics and urine flow rate. MAP was higher in
the low-sodium animals (P , 0.05). Mean baseline
sodium excretion was 44% lower in the low-sodium
animals (P . 0.05). A trend toward greater urinary
potassium excretion was observed in the low-sodium
dogs. As expected, PRA in the low-sodium dogs was
significantly elevated, being four times greater than
that seen in the normal animals. The PRA measurements for the three sodium-replete groups (groups 1, 2,
and 4) were 3.57 6 0.46, 3.41 6 0.60, and 3.16 6 1.46,
respectively. For the two sodium-depleted groups
Table 1. Baseline hemodynamic and renal function
values in normal and low-sodium dogs
Parameter
Normal
(n 5 20)
Low Sodium
(n 5 12)
MAP, mmHg
GFR, ml/min
RBF, ml/min
RVR, mmHg · ml21 · min
UV, ml/min
UNa1V, µeq/min
UK1V, µeq/min
PGE2 , pg/min
PRA, ng ANG I · ml21 · h21
111 6 3
20.7 6 1.5
85.3 6 6.3
1.44 6 0.11
0.05 6 0.01
12.2 6 2.8
8.5 6 1.1
247 6 32
3.41 6 0.60
120 6 3*
18.9 6 2.1
87.7 6 9.1
1.61 6 0.20
0.05 6 0.01
6.78 6 2.22
11.8 6 1.2
484 6 85*
13.77 6 2.87*
Values are means 6 SE. n, No. of animals; MAP, mean arterial
pressure; GFR, glomerular filtration rate; RBF, renal blood flow;
RVR, renal vascular resistance; UV, urine flow; UNa1V, urinary
sodium excretion; UK1V, urinary potassium excretion; PRA, plasma
renin activity. * P , 0.05 vs. normal.
(groups 3 and 5), they were 12.48 6 3.63 and 13.77 6
2.87, respectively. Renal PGE2 excretion was also significantly elevated in the low-sodium dogs, being approximately doubled (Table 1).
Changes in renal hemodynamics. In the vehicletreated normal animals (group 1), over the duration of
the entire protocol MAP decreased from 108 6 3 to
100 6 5 mmHg (P , 0.05). This time-dependent
decrease was seen in most of the other groups. There
were no other significant changes in MAP with either of
the drug treatments for any of the groups (data not
shown).
The effects of the vehicle, Acet, and Ibu on renal
hemodynamics in the normal and low-sodium dogs are
displayed in Table 2. In the normal animals treated
with the vehicle, RBF and GFR decreased with time.
These changes appeared to be due to the decrease in
MAP because RVR did not change in these animals. In
groups 2 and 3, both Acet and Ibu significantly decreased RBF by ,30% (Table 2, Fig. 1). This change
was seen during Exp 1. This renal vasoconstriction
appeared to be transient with Acet, whereas with Ibu
the changes persisted through Exp 2 (Table 2). In group
4 (low-sodium animals), the decrease in RBF with Acet
was similar to that seen in the group 1 normal animals
(39 6 3%). Ibu, however, had a much more dramatic
effect in the low-sodium animals (group 5), decreasing
RBF by 64 6 10%.
As shown in Table 2, RVR was increased significantly
in normal and low-sodium dogs with either Acet or Ibu.
In both normal (group 2) and low-sodium (group 4)
dogs, Acet resulted in a 50–60% increase in RVR. Ibu,
however, produced a dramatically greater increase in
RVR in the low-sodium dogs (group 5; 270 6 92%)
compared with that seen in the normal animals (group
3; 52 6 18%). Thus, although Acet and Ibu treatment
caused similar increases in RVR in normal animals, Ibu
had a significantly greater effect than Acet on RVR in
the low-sodium condition.
Changes in GFR tended to parallel the responses
noted for RBF (Table 2). GFR was not changed by the
vehicle in normal animals (group 1). In the normal
animals, both Acet and Ibu decreased GFR by ,20–
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bladder was approached through a midline ventral incision,
and both ureters were catheterized. After surgery, the animals were allowed an equilibration period of at least 30 min
before the start of data collection.
Monitoring and analytic procedures. BP was monitored
continuously on a Grass recorder; BP was electronically
meaned to determine MAP. HR was derived from pulsatile BP
by using a Grass electrocardiograph tachograph. Data from
the Grass recorder were digitized (MacLab ADInstruments,
Milford, MA) and stored on computer disk for analysis.
Hematocrit was determined by using a microhematocrit
centrifuge. Plasma and urine samples were assayed for PAH
and inulin concentration. Renal plasma flow and GFR were
estimated by PAH and inulin clearances, respectively. RBF
was calculated from renal plasma flow and hematocrit; renal
vascular resistance (RVR) was calculated as the quotient of
MAP and RBF. Serum and urine samples were analyzed for
sodium and potassium by flame photometry. Plasma renin
activity (PRA) and urine PGE2 concentration were determined by radioimmunoassay (DuPont-NEN, Boston, MA).
Urine was assayed directly, in triplicate, for PGE2 (28). All
renal data are for the left kidney only.
Experimental protocols. Five experimental protocols in
total were performed, and they were designated as groups
1–5. For all groups, the protocol began with a 40-min control
period to establish baseline values. After baseline, a saline
vehicle, Acet (15 mg/kg iv), or Ibu (10 mg/kg iv) was infused in
10 ml of saline over 10 min; a sustaining dose of Acet (5
mg · kg21 · h21 ) was also administered. Administration of the
drug or vehicle was followed immediately by two consecutive
40-min experimental periods (Exp 1 and Exp 2, respectively).
Blood samples were collected from the arterial catheter at the
midpoint of each period; urine was collected over each of the
periods.
Group 1 (n 5 5) served as a control group, having received a
normal-sodium diet and a saline vehicle. Groups 2 (n 5 9) and
3 (n 5 6) consisted of normal-sodium animals, administered
Acet and Ibu, respectively. Groups 4 (n 5 7) and 5 (n 5 5) were
low-sodium dogs, receiving Acet and Ibu, respectively.
Statistical analysis. Repeated-measures ANOVA was used
to determine significant differences between the control and
experimental periods within each group. The Fisher least
significant difference was used as a post hoc test. Comparisons were made across groups (i.e., normal vs. low sodium or
Acet vs. Ibu) by using an unpaired t-test. A difference was
considered significant if P , 0.05. Data are expressed as
means 6 SE.
594
ACETAMINOPHEN AND RENAL FUNCTION
Table 2. Effects of Acet or Ibu on renal hemodynamic
function in normal and low-sodium dogs
Period
RBF,
ml/min
GFR,
ml/min
RVR,
mmHg · ml21 · min
Group 1, normal, vehicle (n 5 5)
Baseline
Exp 1
Exp 2
87.95 6 15.30
81.93 6 14.07
72.32 6 10.85*†
23.12 6 2.81
21.26 6 2.78
17.76 6 1.55*†
1.37 6 0.20
1.39 6 0.23
1.52 6 0.23
Group 2, normal, Acet (n 5 9)
Baseline
Exp 1
Exp 2
82.66 6 10.97
49.35 6 5.00*
60.03 6 6.06*
Baseline
Exp 1
Exp 2
87.04 6 7.33
59.97 6 7.39*
60.68 6 12.68*
18.07 6 2.06
11.07 6 0.97*
16.73 6 2.67†
1.62 6 0.20
2.43 6 0.25*
1.91 6 0.17
Group 3, normal, Ibu (n 5 6)
22.69 6 2.97
16.83 6 1.70*
15.95 6 1.75*
1.24 6 0.09
1.83 6 0.18*
1.90 6 0.23*
Group 4, low sodium, Acet (n 5 9)
103.64 6 12.03
64.40 6 9.39*
70.90 6 10.63*
22.74 6 2.93
17.62 6 3.14*
18.47 6 2.85*
1.29 6 0.19
2.16 6 0.43*
1.87 6 0.30*
Group 5, low sodium, Ibu (n 5 5)
Baseline
Exp 1
Exp 2
65.44 6 11.00
25.28 6 8.53*
47.66 6 11.79*†
13.43 6 1.66
6.18 6 2.11*
10.38 6 1.92*†
2.07 6 0.36
8.40 6 3.18*
3.30 6 1.04
Values are means 6 SE. n, No. of animals; Acet, acetaminophen;
Ibu, ibuprofen; Exp 1 and Exp 2, 1st and 2nd experimental periods,
respectively. * P , 0.05 vs. baseline. † P , 0.05 vs. Exp 1.
30% (Fig. 2, groups 2 and 3) (P , 0.05). In the
low-sodium dogs (group 4), the decrease in GFR with
Acet was the same as that seen in normal animals
(26 6 5%). In the low-sodium animals (group 5), Ibu
caused an exaggerated response, with GFR decreasing
by 58 6 11% (P , 0.05) in Exp 1.
Changes in renal excretory function. As shown in
Table 3, in the three groups of normal animals, neither
the vehicle, Acet, nor Ibu had any significant or consistent effects on urine volume, sodium, or potassium
excretion. In contrast, in the low-sodium animals
(groups 4 and 5), both Acet and Ibu significantly
decreased urine flow rate. Both of these changes were
transient, with the values returning to baseline during
Exp 2. In the low-sodium animals, both drugs tended to
decrease sodium and potassium excretion, an effect
that was not seen by Exp 2.
Changes in PGE2 excretion. In the vehicle-treated
normal animals (group 1), baseline PGE2 excretion was
221 6 27 pg/min (Table 4). This value was not significantly different from the baseline PGE2 measurements
for the normal dogs in the Acet and Ibu groups (groups
2 and 3, respectively). In the normal dogs the vehicle
did not alter PGE2 excretion, whereas both Acet and
Ibu reduced PGE2 excretion by ,45% (P , 0.05). In the
normal dogs (group 3), Ibu had a greater and more
prolonged effect on PGE2 excretion than did Acet
(group 2). During Exp 2, PGE2 excretion after Ibu was
approximately one-third of that seen in the Acet group.
The low-sodium animals (groups 4 and 5) had elevated baseline PGE2 excretion rates that were approximately double that seen in the normal animals (Tables 1
DISCUSSION
Under certain normal and pathophysiological conditions, when there is an elevation of peripheral and/or
renal sympathetic nerve activity or enhanced levels of
ANG II, vasodilatory renal PGs are important determinants of renal function (9). In these renal PG-dependent conditions, drugs that inhibit renal PG synthesis,
such as nonsteroidal anti-inflammatory drugs, may
cause severe renal vasoconstriction and salt and water
retention (25).
Acet is a widely used mild analgesic that has long
been available as an over-the-counter product. Because
its inhibitory effects on peripheral PG synthesis are
thought to be minimal, Acet is considered less likely to
have adverse effects on kidney function in renal PGdependent states (27). The data on the effects of Acet on
renal PG synthesis and renal function, however, are
limited. Although Fitzpatrick and Wynalda (10) reported that Acet does not affect renal PGE2 synthesis in
animals in vivo, other investigators have shown that
Acet inhibits renal PG synthesis both in vitro (16) and
in vivo (31). However, in these studies, renal PGE2
synthesis is reduced to a lesser degree by Acet than by
other analgesics and/or anti-inflammatory drugs. In
Fig. 1. Effects of acetaminophen (Acet, 15 mg/kg) or ibuprofen (Ibu,
10 mg/kg) on renal blood flow in normal or low-sodium dogs. Values
shown represent %change from baseline period compared with
average value of entire experimental period [1st and 2nd experimental periods (Exp 1 and Exp 2, respectively)] for each of the 5 groups.
Open bar, control (baseline); solid bars, Acet; hatched bars, Ibu. * P ,
0.05 vs. baseline. † P , 0.05 vs. Acet. § P , 0.05 vs. normal-Ibu.
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Baseline
Exp 1
Exp 2
and 4). In the low-sodium animals both drugs significantly decreased PGE2 excretion to levels that were
comparable to that seen in the drug-treated normal
dogs. During Exp 2, mean PGE2 excretion in the Ibu
group (group 5) was 39% lower than that seen with
Acet (group 4) (P . 0.05).
595
ACETAMINOPHEN AND RENAL FUNCTION
Table 4. Effects of Acet or Ibu on renal PGE2 excretion
in normal and low-sodium dogs
PGE2 Excretion, pg/min
Normal
Period
Vehicle
Acet
Low-sodium
Ibu
Acet
Ibu
Baseline 221 6 27 306 6 60 188 6 12 472 6 96† 503 6 171†
Exp 1
159 6 16 151 6 16*
83 6 14* 148 6 21* 116 6 42*
Exp 2
172 6 16 189 6 35*
57 6 5*
160 6 28*
98 6 28*
Values are means 6 SE. * P , 0.05 vs. baseline within same group.
† P , 0.05 vs. vehicle baseline.
normal healthy humans, Acet has been reported to
decrease (15, 23) or to have no effect on urinary PGE2
excretion (2). Acet has no significant effect on RBF or
GFR in healthy subjects (2, 23); however, there exist
Table 3. Effects of Acet or Ibu on renal excretory
function in normal and low-sodium dogs
Period
UV,
ml/min
UNa1V,
µeq/min
UK1V,
µeq/min
Group 1, normal, vehicle (n 5 5)
Baseline
Exp 1
Exp 2
0.08 6 0.02
0.08 6 0.02
0.08 6 0.01
23.61 6 8.20
20.06 6 9.24
18.65 6 0.67
9.78 6 2.27
10.54 6 0.99
9.99 6 1.19
Group 2, normal, Acet (n 5 9)
Baseline
Exp 1
Exp 2
0.05 6 0.01
0.04 6 0.01
0.05 6 0.01
Baseline
Exp 1
Exp 2
0.04 6 0.01
0.04 6 0.02
0.04 6 0.01
Baseline
Exp 1
Exp 2
0.06 6 0.01
0.04 6 0.01*
0.06 6 0.01†
Baseline
Exp 1
Exp 2
0.04 6 0.01
0.01 6 0.00*
0.03 6 0.01*†
7.71 6 2.87
8.09 6 4.19
9.94 6 4.50
10.03 6 1.86
6.91 6 0.89
10.50 6 1.62
Group 3, normal, Ibu (n 5 6)
9.45 6 1.55
13.93 6 4.89
16.03 6 3.22
5.14 6 0.63
6.02 6 0.55
7.64 6 0.95*
Group 4, low sodium, Acet (n 5 9)
10.72 6 3.44
6.29 6 1.63
12.14 6 3.06†
12.47 6 1.85
10.41 6 1.95
14.09 6 1.80†
Group 5, low sodium, Ibu (n 5 5)
1.25 6 0.38
0.50 6 0.05
2.25 6 0.98†
10.90 6 1.78
4.48 6 1.32*
10.42 6 3.15†
Values are means 6 SE. n, No. of animals. * P , 0.05 vs. baseline.
† P , 0.05 vs. Exp 1.
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Fig. 2. Effects of Acet (15 mg/kg) or Ibu (10 mg/kg) on glomerular
filtration rate in normal or low-sodium dogs. Values shown represent
%change from baseline compared with Exp 1 for each of the 5 groups.
Bars and symbols are defined as in Fig. 1.
isolated case reports of acute nephrotoxicity resulting
from therapeutic Acet use in healthy subjects (3) and in
patients with cardiac and renal insufficiency (6, 16a) or
alcoholic cirrhosis (12), although these cases are complicated by many factors.
Surprisingly, we were unable to identify any studies
that have examined the effects of Acet on kidney
function and PG synthesis in an animal model of a
renal PG-dependent state. Consequently, the purpose
of this study was to evaluate the effects of Acet under
these conditions.
In this study, we used the anesthetized, sodiumdeficient dog as a model of a renal PG-dependent state.
Although anesthesia alone does render the kidneys PG
dependent, sodium depletion heightens the effect by
elevating both PRA and renal sympathetic nerve activity (19). Also, increased basal urinary PGE2 excretion is
seen with the low-sodium diet (4). In this model, it has
been repeatedly shown that drugs that inhibit renal PG
synthesis, such as indomethacin (19) and meclofenamate (4), adversely affect kidney function. As expected,
a significantly greater baseline PRA was observed in
the low-sodium dogs; however, on the basis of a mean
PRA of ,14 ng ANG I · ml21 · h21, these animals were
clearly only moderately stressed in this regard. In
addition, basal PGE2 excretion was more than doubled
in the low-sodium animals. With increased PGE2 synthesis, it would be expected that blockade of PG synthesis would have greater effects on RBF and GFR in the
low-sodium animals compared with the normal animals.
The variability across the groups in their baseline
sodium excretion (Table 3) was unexpected. The reason
for these differences, especially among the replete
groups, is unknown. What is important, in terms of
being able to make fair comparisons of the drugs tested
across the groups, is whether the renin-angiotensin
systems were similarly or differentially activated in the
normal or depleted groups. This parameter is probably
more important than basal sodium excretion because
PRA values are directly linked to, and are predictive of,
the amount of renal vasoconstriction seen with PG
inhibition (5). As indicated in RESULTS, PRA values were
similar for the three groups of normal, sodium-replete
dogs, ranging from 3.16 to 3.57 ng ANG I · ml21 · h21,
whereas in the two groups of depleted animals the PRA
values were 12.48 and 13.77 ng ANG I · ml21 · h21. These
data are important because they demonstrate that the
596
ACETAMINOPHEN AND RENAL FUNCTION
dose of Ibu was effective, reducing PGE2 excretion by
70–80%.
A methodological concern pertains to the fact that
Ibu is an inhibitor of anion transport. As such, Ibu could
potentially alter PAH transport, change the PAH clearance values, and thus invalidate the use of PAH
clearance to measure RBF. In this study we did not
sample renal venous blood to determine PAH extraction. However, we believe that the declines in RBF
observed with Ibu are real and not due to this possible
artifact. A strong argument in support of this position is
that the declines in GFR and RBF, shown in Figs. 1 and
2, are essentially superimposable. Because inulin clearance, unlike PAH clearance, cannot be affected by this
potential problem, this suggests that the declines in
PAH clearance were reflecting changes in RBF.
This study is the first to show that Acet may compromise renal function in a renal PG-dependent animal
model. The renal vasoconstriction observed with Acet
in the low-sodium animals was associated with an
inhibition of renal PG synthesis, as estimated by PGE2
excretion. Although the effects of Acet were far less
than that seen with Ibu, these data do suggest that Acet
has the potential to decrease renal PG and possibly
adversely affect renal function under certain conditions.
These results suggest that a more careful or closer
inspection is warranted concerning the effects of Acet
on renal function in humans when the renal sympathetic nerves and the renin-angiotensin system are
both maximally activated, either because of environmental conditions such as dehydration, heat stress, or
exercise or as a consequence of a disease state, such as
congestive heart failure or cirrhosis.
This study was supported in part by a gift from McNeil Consumer
Products Co.
Address for reprint requests: E. J. Zambraski, Dept. of Cell Biology
and Neuroscience, Rutgers, State Univ. of New Jersey, Nelson
Laboratories, 604 Allison Road, Piscataway, NJ 08855-8082 (E-mail:
[email protected]).
Received 19 March 1998; accepted in final form 7 October 1998.
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animals were similarly stressed (depleted) or nonstressed (normal, replete) in the various treatment
groups, despite the large variability in sodium excretion.
Under the conditions of this study, both Acet and Ibu
reduced GFR and RBF in the normal, sodium-replete
dogs. Anesthesia and surgical stress may have been the
factors involved in this response. Pentobarbital anesthesia stimulates the renin-angiotensin system (7), thus
producing a mild renal PG-dependent state. Laparotomy also has been shown to increase renal PG
synthesis in dogs (27). The differences between Acet
and Ibu were clearly seen in the low-sodium animals.
In these animals Acet had effects similar to that in the
normal dogs. In contrast, Ibu caused a markedly greater
renal vasoconstriction in the low-sodium animals. The
declines in both GFR and RBF were significantly
greater with Ibu compared with Acet (Figs. 1 and 2). In
the low-sodium dogs Ibu increased RVR fourfold,
whereas this value increased by only 67% with Acet
(Table 2). These data demonstrate that both drugs
cause renal vasoconstriction in animals whose renal
function is PG dependent; the effects, however, are
dramatically more severe with Ibu.
Surprisingly, Acet and Ibu reduced urinary PGE2
excretion to comparable levels in both normal and
low-sodium dogs. This response is similar to that
reported by Blasingham et al. (5) and Blasingham and
Nasjletti (4) using meclofenamate. Although the decrease in PGE2 excretion as a percentage of baseline
values was greater in the low-sodium animals, this was
a function of their higher baseline PGE2 levels. Ibu
tended to have a greater and more prolonged effect on
PGE2 excretion in both sodium states. This finding is
consistent with in vivo data (10) in which Ibu produced
a greater suppression of PGE2 synthesis in rat kidney
than did Acet.
When Ibu vs. Acet is compared under these conditions, the issue of dosage is an important factor. The
therapeutic dose of Acet can be as high as 4,000 mg/day
(22). Nielsen et al. (18) observed that a maximum
analgesic effect of Acet was reached 2 h after oral
administration of a single therapeutic dose (500–1,000
mg). At maximum effect, plasma concentration of Acet
was 8–10 µg/ml. The intravenous dose of Acet used in
this study has been shown to result in plasma Acet
concentrations in this therapeutic range (22, 23). Because the half-life of Acet after intravenous administration has been shown to be ,30 min (22, 25), a sustaining solution of Acet (5 mg · kg21 · h21 ) was utilized to
maintain therapeutic levels of the drug throughout the
full duration of the experiment. The dose of Ibu used
(10 mg/kg) was selected on the basis of our prior work
using this compound. In an earlier study (29), 20 mg/kg
of Ibu were utilized, and this dose decreased renal
PGE2 excretion by .90%, an effect similar to what was
seen with 10 mg/kg of naproxen. In subsequent tests, it
was determined that a 10 mg/kg dose of Ibu achieved
renal PG inhibition ranging from 70 to 90%; therefore,
we chose to use the lower dose. Table 4 shows that this
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