Vol. 86, Issue 6, 1936-1943, June 1999
Age and renal prostaglandin inhibition during exercise and
heat stress
W. B.
Farquhar and
W. L.
Kenney
Noll Physiological Research Center, Pennsylvania State
University, University Park, Pennsylvania 16802-6900
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ABSTRACT |
Aging is associated with a number of
physiological changes that may cause the kidney to rely to a greater
extent on vasodilatory PGs for normal functioning. Acute exercise has
been shown to cause renal vasoconstriction that may be partially
buffered by vasodilatory PGs. To determine the relative importance of
renal PGs during exercise in older adults, we compared the renal
effects of the PG inhibitor ibuprofen (1.2 g/day for 3 days) vs. a
placebo control in a cohort of eight younger (24 ± 2 yr) and eight
older (64 ± 2 yr) women during treadmill exercise (~57% maximal
oxygen consumption) in the heat (36°C). This over-the-counter dose
of ibuprofen reduced renal PG (i.e.,
PGE2) excretion by 47%
(P < 0.05). Acute exercise in the
heat caused dramatic decreases in glomerular filtration rate, renal
blood flow, and sodium excretion in both age groups. PG inhibition was
associated with greater decreases in urine production and free water
clearance (P < 0.05). There were no
drug-related declines in glomerular filtration rate or renal blood
flow. We conclude that PG inhibition has only modest effects on renal
function during exercise. Also, the lack of hemodynamic changes with PG inhibition indicates that healthy well-hydrated older women are not in
a renal PG-dependent state.
glomerular filtration rate; renal hemodynamics; ibuprofen; nonsteroidal anti-inflammatory drugs
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INTRODUCTION |
WE PREVIOUSLY REPORTED (9) that an over-the-counter
(OTC) dose of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen (Ibu) depresses glomerular filtration rate (GFR) more than does a
placebo (Pl) in a cohort of younger men and women during dehydrating exercise in the heat. Under these conditions, Ibu caused a 41 ± 2%
decrease in GFR compared with a 31 ± 3% decrease in the Pl trial.
Walker et al. (29) found that the NSAID indomethacin lowered renal
blood flow (RBF), concluding that with sustained exercise indomethacin
can compromise renal function and potentiate the risk of developing
acute renal failure. There have also been anecdotal case reports
linking NSAID use to acute renal failure during prolonged exercise (20,
27). Although effects are negligible under nonstressed conditions (35),
NSAIDs such as Ibu and indomethacin have been shown to inhibit
vasodilatory renal PGs, such as
PGE2 and
PGI2, up to 60% and to depress
renal function during what have been termed renal PG-dependent states
(21). Frequently cited examples of PG-dependent states include
hypovolemia, salt depletion, chronic heart failure, and hepatic
cirrhosis (7, 16, 28, 37), all of which are characterized by enhanced sympathetic outflow, increased circulating catecholamine
concentrations, and increased angiotensin II. PGs are thought to
partially modulate renal function during these high vasoconstrictor states.
Many of the physiological changes that accompany aging might be
predicted to increase the kidney's reliance on PGs, leading some to
classify aging as a PG-dependent state. For example, aging is
associated with decreases in GFR, RBF, and blood flow per unit mass of
the kidney (8, 14, 18). In addition, the progressive loss of
functioning nephrons in the older kidney increases the fluid and solute
load per nephron (8). This decreases the functional reserve of the
kidney and, assuming that this loss is analogous to the experimental
reductions in renal mass in animals (i.e., two-thirds nephrectomy), may
enhance the ability of NSAIDs to facilitate vasoconstriction (31).
Also, at rest arterial plasma norepinephrine spillover rates are
elevated in the older adult (26), possibly leading to enhanced renal
vasoconstriction. However, the limited data do not support a direct
link between NSAID use and renal dysfunction in healthy older adults
during resting conditions. Asokan et al. (2) administered 75 mg/day of
indomethacin for 1 wk to 10 healthy older adults (mean age 71 yr, 7 women and 3 men). No changes in GFR and renal plasma flow (RPF) were
reported in the indomethacin trial compared with the Pl control. Allred et al. (1) reviewed patient data from 27 women (mean age 84 yr) taking
NSAIDs for at least 3 wk and compared them with 27 control subjects
(mean age 85 yr). There were no differences in serum urea, creatinine,
or potassium concentrations between the two groups. Therefore, at least
under resting conditions in the older adult, NSAIDs do not appear to
impair renal function.
The purpose of the present study was to determine whether NSAIDs
depress renal function during exercise and heat stress in the healthy
older adult. Heat stress combined with exercise is associated with
greater decreases in RBF and GFR compared with exercise in normothermic
conditions. Exercise is associated with increased renal sympathetic
activity, increased circulating catecholamine concentrations, and
increased renin-angiotensin II, which, as stated above, may be
predicted to evoke a renal PG-dependent state. The aforementioned
physiological changes seen with aging would likely augment the
deleterious effects of PG inhibition with NSAIDs. To determine whether
the relative importance of PGs in the control of renal function changes
with advancing age, comparisons between older and younger subjects were
made. We hypothesized the following: 1) PG inhibition with Ibu would not
alter resting renal function (GFR, RBF, and sodium excretion);
2) during exercise, Ibu would cause
greater transient reductions in renal function than a Pl in the older
adult; and 3) renal PGs would play a
greater role in the control of renal function during exercise in the
older kidney, (i.e., a greater decrease in renal function during PG inhibition with Ibu in the older subjects).
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METHODS |
Subjects.
Sixteen healthy women (8 younger and 8 older; see Table
1 for subject characteristics) gave their
oral and written consent to participate in this institutionally
approved study. The older women were postmenopausal and not taking
hormone-replacement therapy. Men were not included in the study because
urinary PGE2 excretion only
reflects urinary PGE2 production
in women [men produce PGs from nonrenal sources such as the
seminal vesicles (33)]. Subject screening was performed under the
auspices of the Noll Laboratory General Clinical Research Center and
consisted of a physical examination by a physician, resting
electrocardiogram (ECG), body composition assessment using skinfold
calipers (15), and a maximal graded exercise test on a motor-driven
treadmill where the ECG was monitored for the older subjects only.
Maximal oxygen consumption
(
O2 max) was measured
during this initial exercise test by using an automated online system.
The treadmill protocol consisted of a 4-min warm-up followed by 2-min
stages where speed was held constant and grade increased 2-2.5%
per stage until the subject was no longer able to continue. Respiratory
exchange ratio values for all subjects at peak exercise exceeded 1.05. A complete blood count (Coulter MicroDiff 16, Coulter, Miami, FL),
Chem-24, and a 24-h urine creatinine clearance (American Medical
Laboratories) were also performed as part of the initial screening
process. A pregnancy test was performed on the younger subjects. Only
subjects with no past history of any chronic disease, a normal exercise
test, normal baseline venous electrolyte concentrations, and no
evidence of kidney or liver dysfunction were accepted into the study.
Also, none of the subjects were taking any OTC or prescription
medications.
Protocol.
Each subject completed two randomized double-blind trials that were
identical in all respects except that in one trial the maximal OTC dose
of generic Ibu (400-mg doses ×3, for a total of 1.2 g/day) was given,
whereas in the other trial an identical-looking lactose-filled caplet
was given (Pl trial). Drug or Pl administration started 2 full days
before the exercise trial and continued the day of the experimental
trial (for a total of 3 days of the maximum OTC dose). Subjects were
instructed to eat and drink normally during the preceding 2 days.
Subjects collected their urine for a 24-h period the day before the
experimental trial for subsequent analysis of urine production, sodium
and potassium excretion, and creatinine clearance. Each trial was
separated by ~1 mo. Because fluid balance and hormonal concentrations
fluctuate during the normal menstrual cycle, all younger subjects
performed the study during the early follicular phase (self-reported;
before day 8) of their menstrual
cycle, when estrogen and progesterone concentrations are relatively low.
The experimental day started at 0600 with the subjects eating a
standard breakfast, drinking 7 ml/kg of water, and receiving 400 mg of
Ibu or Pl. Pill administration was repeated at 1000 and
again at 1330 (~30 min before the start of exercise). Subjects had a
standard light snack and 7 ml/kg of water at 1030. At ~1100, one
indwelling catheter was placed in each arm, one for the infusion and
one for venous blood sampling. The infusions of inulin and p-aminohippurate sodium (PAH)
(detailed under Procedures) were started at ~1200 and continued until 1600 h. Blood and urine samples were periodically collected (also detailed under
Procedures). The first 2 h
[dry bulb temperature = 25°C] were used to establish baseline resting renal function, the third hour consisted of renal function measures during exercise in the heat (dry bulb temperature = 36°C, wet bulb temperature = 24°C), and the fourth and final hour was recovery from exercise (dry bulb temperature = 25°C). All
subjects were weighed (scale accuracy ± 50 g) immediately before
and after the 4-h infusion. The exercise bout consisted of 1 h of
treadmill (TM) walking (jogging for 1 of the younger subjects).
Absolute TM workload (speed and grade) for each subject was
individually calculated to elicit 60%
O2 max by using the American College of Sports Medicine metabolic equations (17). Exercise
intensity was verified by collecting expired air for 4 min into two
Douglas bags (20 min into exercise) for subsequent O2 concentration,
CO2 concentration, and volume
analysis. A 5-min break was taken 30 min into the exercise bout to
obtain a urine sample and to provide the subject with 7 ml/kg of water.
The same volume of water was also given at the start of the 1-h
recovery period.
Procedures.
RPF and GFR were determined by using PAH (Merck, West Point, PA) and
inulin (Cypros Pharmaceutical, Carlsbad, CA), respectively. Steady-state plasma levels of PAH and inulin were achieved by using a
bolus priming injection (5.6 mg/kg of PAH and 45 mg/kg of inulin)
followed by a constant infusion (Harvard Apparatus 22, South Natick,
MA) of the substances mixed in a 0.9% sodium chloride solution (Abbott
Laboratories, North Chicago, IL). The infusion rates for inulin and PAH
were based on estimated baseline GFR (determined via 24-h creatinine
clearance) and RPF (24-h creatinine clearance × 5) and therefore
varied for each subject. At 50 min into the infusion, the subjects
emptied their bladder and the first timed urine collection period
began. There were two urine collection (clearance) periods lasting
~30 min each during rest, exercise, and recovery. Blood samples were
collected before the start of the infusion (preblood) and at the
midpoint of each clearance period: at 75 and 105 min into the infusion
for the resting renal function measures, 15 and 45 min during the 1 h
of exercise, and 15 and 45 min into the recovery. RPF, GFR, and RBF
were calculated by using the following formulas
![RPF = ([U]<SUB>PAH</SUB>/[P]<SUB>PAH</SUB>) ⋅ V)/0.90](/content/vol86/issue6/fulltext/1936/img001.gif)
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![GFR = ([U]<SUB>inulin</SUB>/[P]<SUB>inulin</SUB>) ⋅ V](/content/vol86/issue6/fulltext/1936/img002.gif)
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where
[P]PAH,
[U]PAH,
[P]inulin, and
[U]inulin are the
plasma and urine concentrations of PAH and inulin, respectively
(mg/dl); V is the urine flow rate in milliliters per minute; and Hct is the hematocrit. An extraction ratio of 0.90 was used for PAH when calculating RPF, which has been previously shown to not change during
moderate-intensity exercise (4, 13). PAH and inulin were assayed using
standard spectrophotometric techniques (5, 30). A continuous-flow
autoanalyzer (Technicon Instruments, Tarrytown, NY) and a
spectrophotometer (Spectronic 21D-Milton Roy, Rochester, NY) were
utilized for the PAH and inulin assays, respectively. Hemodynamic
variables were all standardized to a body surface area of 1.73 m2. Filtration fraction (%) was
calculated as (GFR/RPF) · 100.
All blood samples were collected into EDTA-containing,
heparin-containing, and serum-separator vacutainers (Becton Dickinson, Franklin Lakes, NJ) and immediately placed on ice. Hemoglobin concentration and Hct were determined by using a Coulter hematology analyzer (Coulter MicroDiff 16, Coulter, Miami, FL). All samples were
subsequently centrifuged, and the plasma was frozen. Urine volume was
measured by using a graduated cylinder with an aliquot frozen in 15-ml
polypropylene Falcon tubes (Becton Dickinson, Franklin Lakes, NJ).
Rectal temperature (Tre) was
used as an index of core temperature. A rectal thermistor (YSI series
400) was inserted by the subjects 10 cm past the anal sphincter. A
temperature-controlled water bath (verified with a mercury thermometer)
was used to calibrate the thermistor.
Tre was recorded before, every 5 min during, and every 10 min after exercise. Heart rate was recorded
before, every five 5 during, and every 10 min after exercise by using a
Polar monitor in the younger subjects and a single-lead ECG (CM5,
Marquette Electronics) in the older subjects.
Serum and urine osmolality were determined by using the freezing-point
depression technique with an Advanced DigiMatic Osmometer model 3D2
(Advanced Instruments, Norwood, MA). Free water clearance (CLH2O) was
calculated by using the following formula
where
Uosm and
Posm are equal to urine and plasma
osmolality, respectively
(mosmol/kgH2O).
Percent change in plasma volume (resting in the seated position vs.
exercise in the standing position) was calculated by using the changes
in the hemoglobin concentration and Hct (6). Because posture was not
the same during the resting and exercise periods, it is not possible to
determine the independent effects of exercise on plasma volume.
Creatinine concentration for the 24-h urine sample was determined by
using standard spectrophotometric techniques with a continuous-flow
autoanalyzer (Technicon Instruments, Tarrytown, NY; Jaffe method) and
used to estimate GFR on the day preceding the experimental trial.
Sodium and potassium concentrations were measured by using an automatic
flame photometer (model IL943TM, Instrumentation Laboratories, Lexington, MA). PGE2 concentration
in the urine (34) was measured by using a commercially available
radioimmunoassay
[125I] kit (DuPont
Medical Products, Boston, MA). All excretion rates were calculated
using the following formula: volume (l) · time (min)
1 · concentration
(meq/l or pg/ml).
Statistical analysis.
All data are reported as means ± SE. A repeated-measures ANOVA (SAS
statistical software) was used to determine age, drug, and time effects
(2 × 2 × 5; there were actually 6 clearance periods, but
only 1 resting clearance period was used for analysis to simplify the
model). A P value of 0.05 was
considered significant. Differences in physical characteristics between
younger and older subjects were determined by using a two-tailed
independent t-test. Because time was
not a factor for the variables determined from the 24-h urine sample as
well as changes in plasma volume and
PGE2 excretion, a two-tailed
dependent t-test was used to evaluate
drug effects. Post hoc comparsions were done by using the
Scheffé's method.
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RESULTS |
Subject characteristics are presented in Table 1. As expected, baseline
24-h creatinine clearance was significantly lower in the older
subjects. Older subjects also had a higher percent body fat and a lower
O2 max
(P < 0.05).
Urine production from the 24-h urine samples collected on the day
before the experimental trial (1 day after the start of Ibu or Pl) was
consistently lower in the Ibu trial (compared with the Pl trial) for
both the younger and older subjects (in 14 of 16 subjects): 1.1 ± 0.2 and 1.3 ± 0.2 ml/min in the older and 0.9 ± 0.1 and 1.2 ± 0.2 ml/min in the younger for the Ibu and Pl trials, respectively
(P < 0.05). Sodium excretion was
58 ± 5 and 79 ± 9 meq/min in the older
(P > 0.05, Pl vs. Ibu) and 91 ± 9 and 103 ± 13 meq/min in the younger
(P > 0.05, Pl vs. Ibu) during the
Ibu and Pl trials, respectively (no statistical differences). Creatinine clearance from the 24-h urine sample was 96 ± 6 and 103 ± 8 ml · min1 · 1.73 m2 in the younger subjects
and 71 ± 8 and 62 ± 10 ml · min1 · 1.73 m2 in the older subjects
during the Ibu and Pl trials, respectively, representing a significant
age (P < 0.05) effect but no drug
effect. Renal PGE2 production was
significantly lower in the Ibu compared with the Pl trial
(P < 0.05; see Fig.
1).
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Fig. 1.
Individual (and mean ± SE) urinary
PGE2 excretion in the older ( ,
n = 7) and younger ( ,
n = 8) subjects. The 24-h urine sample
was collected 1 day after ibuprofen (Ibu; 1.2 g/day) was started.
* P < 0.05, placebo (Pl) vs.
Ibu.
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Resting measures during the infusion on the experimental day indicated
that older subjects excreted less sodium (Fig.
2) and had a significantly lower GFR (Fig.
3) and RBF (Fig.
4; P < 0.05). Urine production (Fig. 5) and free
water clearance (Fig. 6) were similar in
the older and younger subjects. Filtration fraction averaged 28% in
the younger subjects and 29% in the older subjects (with no drug
effect).
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Fig. 2.
Sodium excretion in younger (A;
n = 8) and older
(B; n = 8) subjects during resting conditions, exercise (2 clearance
periods), and recovery (also 2 clearance periods). PL, placebo; IBU,
ibuprofen. Values are means ± SE. Repeated-measures ANOVA indicated
significant age ( P < 0.007) and time (* P < 0.0001) effects as well as significant interactions between age and
drug (P < 0.02) and age and time
(P = 0.0001).
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Fig. 3.
Glomerular filtration rate (GFR) in older
(n = 8) and younger
(n = 8) subjects during resting
conditions, exercise (2 clearance periods), and recovery (also 2 clearance periods). Values are means ± SE. Repeated-measures ANOVA
indicated significant age
( P < 0.02) and time
(* P < 0.0001) effects as well as a significant age and drug
interaction (P < 0.05).
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Fig. 4.
Renal blood flow (RBF) in older (n = 8) and younger (n = 8) subjects during
resting conditions, exercise (2 clearance periods), and recovery (also
2 clearance periods). Values are means ± SE. Repeated-measures
ANOVA indicated significant age
( P < 0.006) and
time (* P < 0.0001) effects as
well as a significant age and time interaction
(P < 0.0001).
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Fig. 5.
Urine production in younger (A;
n = 8) and older
(B; n = 8) subjects during resting conditions, exercise (2 clearance
periods), and recovery (also 2 clearance periods). Values are means ± SE. Repeated-measures ANOVA indicated significant drug
( P < 0.03) and
time (* P < 0.0001) effects.
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Fig. 6.
Free water clearance (CL H2O) in
younger (A;
n = 8) and older
(B; n = 8) subjects during resting conditions, exercise (2 clearance
periods), and recovery (also 2 clearance periods). Values are
means ± SE. Repeated-measures ANOVA indicated
significant drug ( P < 0.02) and time (* P < 0.0001)
effects. § Significant differences between Pl and Ibu trials,
P < 0.05 (post hoc comparison).
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Exercise in the heat caused dramatic decreases in GFR, RBF, urine
production, sodium excretion, and free water clearance in both age
groups (P < 0.0001). Ibu depressed
urine production (P < 0.03 vs. Pl)
and free water clearance (P < 0.02 vs. Pl) in both age groups. No drug effects were seen for RBF, GFR, and
sodium excretion in either age group.
PGE2 excretion during exercise was
83.3 ± 18.5 and 53.9 ± 17.9 pg/min in the Pl and Ibu trials, respectively. Although these excretion values tended to be lower in the
Ibu trial, they did not reach significance
(P > 0.10). Preexercise rectal
temperatures in the younger subjects were 37.19 ± 0.09 and 37.28 ± 0.04°C and increased during exercise to 38.74 ± 0.08 and
38.81 ± 0.10°C in the Ibu and Pl trials, respectively, with no
drug effect. The older subjects' preexercise rectal temperatures were
36.91 ± 0.07 and 36.94 ± 0.12°C (Ibu and Pl trials,
respectively) and increased to 38.50 ± 0.16 and 38.45 ± 0.13°C during exercise. Although no drug effects were noted for
either age group, the older group's preexercise and exercise
temperatures were significantly lower than those of the younger
subjects. Preexercise heart rates were not affected by drug or age and
averaged 76 beats/min. Peak exercise heart rates were 164 ± 3 and
158 ± 4 beats/min in the younger subjects and 132 ± 8 and were
133 ± 8 beats/min in the older subjects in the Ibu and Pl trials,
respectively, representing a similar percentage of maximal heart rate
in the older and younger subjects. Oxygen consumption was 24.6 ± 2.0 and 25.0 ± 1.8 ml · kg1 · min1
in the younger subjects and 15.8 ± 1.6 and 15.8 ± 1.3 ml · kg1 · min1
in the older subjects during the Ibu and Pl trials, respectively. This
represented ~55 and 60%
O2 max for the older
and younger subjects, respectively. Percent change in plasma volume was
13 ± 2 and 10 ± 2% in the younger and 2 ± 2 and 8 ± 2% in the older subjects for the Ibu and Pl
trials, respectively. The only drug effect was a smaller change in
plasma volume in the older subjects during the Ibu trial
(P < 0.03).
All measured and calculated variables started to return to baseline
during the 1-h recovery period. Ibu appeared to have longer lasting
effects in the older subjects, demonstrated by the depressed urine
production and free water clearance in the second recovery clearance period.
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DISCUSSION |
This purpose of this study was to investigate the renal effects of PG
inhibition with OTC Ibu during exercise in older adults. Because NSAID
use among younger and especially older adults is prevalent (12), it was
thought that this type of investigation would yield usable information
for these populations. Another aim was to understand the importance of
renal PGs in the regulation of the kidney during exercise and to
determine whether this changed with advancing age.
Renal PGs can be important determinants of renal function during
certain physiological and pathological conditions; therefore, inhibiting PGs with NSAIDs can depress renal function. By using exercise and heat stress as physiological perturbations, we predicted that PG inhibition would have a selectively greater effect in the older
adults due to an age-related decrease in renal function. The major
finding of this study was that OTC Ibu inhibited renal PG production
and caused significant decreases in urine production and free water
clearance. Contrary to what we anticipated, Ibu did not depress GFR or
RBF in either age group. The lack of a significant Ibu-induced change
in GFR was demonstrated under resting conditions via 24-h creatinine
clearance the day preceding exercise and with inulin clearance on the
experimental day. Although there are no comparative data in older
adults, Zambraski et al. (36) found that aspirin use was associated
with minor changes in free water clearance but no changes in creatinine
clearance after treadmill exercise in nonhydrated (no food or drink for
10 h before exercise) younger men. These results also differ from our
earlier work (9), where a slightly lower GFR was found with Ibu in
younger subjects during exercise. However, the previous subjects were
dehydrated before the exercise bout; therefore the kidney was probably
stressed to greater extent in the prior report (9).
Ibu-induced reductions in urine production and free water clearance may
have been mediated through the actions of arginine vasopressin (AVP).
Previous studies (3, 10) report that PGs inhibit the intrarenal actions
of AVP on the collecting tubule within the renal medulla. Therefore,
when renal PG production declines, there is a release of inhibition of
AVP, which results in enhanced water reabsorption. Because this
probably occurs without any appreciable change in circulating AVP, we
did not attempt to measure plasma AVP concentration.
There was a significant (P < 0.02)
age and drug interaction in sodium excretion. Sodium excretion was
slightly higher at each of the five time points (rest, exercise,
and recovery; see Fig. 2) in the younger subjects during the
Ibu trial but lower at four of the five time points in the older
adults. Sodium excretion the day before exercise (24-h urine sample)
was 12 (P > 0.05) and 27%
(P > 0.05) lower in the Ibu trial in
the younger and older subjects, respectively. PGs have been previously
shown to be natriuretic, and PG inhibitors often cause sodium
retention, although controversy exists regarding the mechanism(s)
involved. Scherzer et al. (25) reported that indomethacin causes sodium
retention through activation of
Na+-K+-ATPase
activity in the tubular cells, which augments sodium transport across
the basolateral membrane. These data imply that renal PGs normally
function to inhibit
Na+-K+-ATPase
pump activity. The cause of the slightly greater sodium excretion in
the younger during the infusion is not known, but the aforementioned
mechanism could explain the Ibu-induced reduction in sodium excretion
in the older subjects.
Renal PGE2 excretion has been
shown to be a valid index of renal
PGE2 production in female dogs
(34) and has therefore been used as a surrogate measure of renal
PGE2 production in humans (33).
The ability of OTC Ibu to inhibit renal
PGE2 excretion in the present
study is shown in Fig. 1. During exercise, the response was more
variable, especially in the younger subjects. These variable responses
were also noted by Zambraski et al. (33) in a cohort of younger women
during exercise. Nevertheless, in the present study, Ibu was associated
with a 36% reduction (P > 0.10) in
PGE2 excretion. Similarly, in a
related exercise study, Poortmans et al. (23) found a 75% reduction in
PG 6-keto-F1
excretion after 2 min of strenuous exercise in a group of 10 healthy men taking Ibu
(compared with a Pl). However, because Ibu and other NSAIDs do not
completely abolish renal PG synthesis, the remaining PGs may still
contribute to the control of renal function.
These data do not support the notion that older adults are in a
constant PG-dependent state under basal or exercise conditions. PG-dependent states are usually characterized by significant declines in renal hemodynamic function and profound sodium retention with the
administration of a PG inhibitor, neither of which occurred within this
cohort of older adults.
The exercise protocol utilized caused dramatic reductions in renal
function in both age groups. In the Pl trial, GFR and RBF decreased
~30-50%. Similarly, urine production decreased 60-70% in
both age groups. Declines in renal function during exercise are
intensity dependent (11) and generally in the range of 30-60% (32). The slightly greater reductions in urine production in the
present study can be attributed to the added burden of heat stress and
the fact that all subjects were very well hydrated, as evidenced by the
high urine flow rates preceding exercise (>5.0 ml/min). The subjects
were all well hydrated to avoid dehydration and to ensure adequate
urine volumes for accurate analysis. Nevertheless, the renal responses
were consistent with previous data. For example, Poortmans (22) noted
that urine flow decreased ~80% in hyperhydrated (urine flow
7-17 ml/min) subjects after short but exhaustive exercise.
There was a highly significant (P < 0.0001) age and time interaction for RBF. It appears as though the
return of RBF to baseline in the recovery was sluggish in the older
subjects. A similar response was noted by Kenney and Zappe (18) in
their investigation of younger and older men. At present, no conclusive
mechanistic explanation can be provided, other than stating that PG
inhibition does not alter this response. Overall, few studies (24) have investigated the renal hemodynamic responses to acute exercise in older
adults, especially in postmenopausal women. These data are therefore
important because they show that older women not taking
hormone-replacement therapy respond in a similar fashion as do younger
women and men.
In summary, OTC Ibu use in well-hydrated older subjects does not result
in declines in renal hemodynamic function during acute exercise. There
are, however, significant changes in the renal handling of water
associated with PG inhibition. There are also age-related changes in
renal sodium handling associated with PG inhibition. The renal effects
of higher anti-inflammatory doses of Ibu and the effects of Ibu during
dehydrating exercise in older adults are not known. In conclusion,
older women do not appear to be in PG-dependent state under basal or
exercise conditions.
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ACKNOWLEDGEMENTS |
The authors thank the subjects for their enthusiastic participation
in the study as well as Esther Asplund, Carla Thomas, Jon Gaffey,
Stacey Wladkowski, Jane Pierzga, and Mark Dunbar for data collection
assistance and support. The biochemical assistance of Marlen
Druckenmiller; the statistical expertise of Li Haihong, Esther
Asplund, and Alex Kartashov; and the editorial comments provided by
Dr. Edward Zambraski are greatly appreciated. The nursing care and
medical support provided by the Pennsylvania State General Clinical
Research Center at the Noll Physiological Research Center is also
gratefully acknowledged.
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FOOTNOTES |
This work was supported, in part, by an American College of Sports
Medicine Graduate Student Foundation Research Grant, the Friedman
Graduate Student Fund at Pennsylvania State, and Division of Research
Resources Grant M01-RR-10732. The PAH was generously donated by Merck.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: W. B. Farquhar, HRCA Research and
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farquhar{at}mail.hrca.harvard.edu).
Received 16 October 1998; accepted in final form 12 February 1999.
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