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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
School of Biological Sciences, University of Manchester, Manchester, United Kingdom
Received February 28, 2003; accepted April 16, 2003.
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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),
often also used to treat rheumatoid arthritis and systemic lupus
erytheromatosis (Ducharme and Farinotti,
1996). In addition to these therapeutic effects, we have shown
that chloroquine has a number of pronounced renal actions that seem to be
mediated, at least in part, by nitric oxide
(Musabayane et al., 1994;
Ahmed et al., 2003a).
Chloroquine infusion in the anesthetized rat resulted in marked increases in
glomerular filtration rate (GFR), urine flow, and sodium excretion rate,
accompanied by a reduction in urine osmolality. All of these responses could
be blocked by the nitric oxide synthase inhibitor
N
-nitro-L-arginine methyl ester,
suggesting that nitric oxide plays a role in mediating these renal actions of
chloroquine (Ahmed et al.,
2003a).
Chloroquine is often taken against a background of chronic nonsteroidal
anti-inflammatory drug (NSAID) ingestion in regions where malaria is
prevalent. NSAIDs such as aspirin and paracetamol (known as acetaminophen in
the United States) are taken regularly to reduce fever associated with
malaria; hence, people living in these regions are likely to ingest
paracetamol on a regular basis over a long period of time
(Chada, 1998;
Eddleston, 2000). One
consequence of this is an increased risk of developing analgesic
nephropathy.
Paracetamol is a rapid, reversible, noncompetitive inhibitor of
cyclooxygenase activity and thus products of the arachidonic acid cascade
(Hardman et al., 2001). At
doses within the therapeutic range, it affects renal function, lowering renal
blood flow, GFR, sodium excretion, and prostaglandin E2 excretion
in both human and the rat (Prescott et
al., 1989; Trumper et al.,
1998). Paracetamol also exerts acute and chronic nephrotoxic
effects. Acute toxicity after ingestion of large doses (10–15 g) is
characterized by necrosis and damage to the proximal tubule. Chronic ingestion
of much lower doses (500–1000 mg) can produce renal damage, resulting in
analgesic nephropathy (Blantz,
1996). This is defined as habitual ingestion of an analgesic,
which after an insidious onset, leads to renal papillary necrosis and chronic
interstitial nephritis with progressive renal failure
(Henrich, 1998).
We have recently described a model of subclinical analgesic nephropathy in
the rat induced by ingestion of paracetamol at 500 mg
kg–1 b.wt. day–1 for
30 days (Ahmed et al., 2003b).
This treatment regime did not produce gross renal histological changes
associated with clinical nephropathy, such as papillary necrosis and
interstitial nephritis, but it did reduce the urinary concentrating ability of
the animals. Previous studies have shown that treatment at this dose for up to
20 weeks is required to induce renal histopathological changes
(Nanra et al., 1973),
reflecting the relative resistance of the rat to analgesic nephropathy.
In the same study (Ahmed et al.,
2003b), we also assessed the effect of chronic paracetamol
treatment on the renal actions of chloroquine. The response to chloroquine of
rats with analgesic nephropathy was markedly different from that in untreated
animals. The diuresis, natriuresis, and increase in GFR seen with chloroquine
alone were all reversed when chloroquine was infused in rats that had
previously been treated with paracetamol
(Ahmed et al., 2003b). This
could be attributable to either the acute inhibitory effect of paracetamol on
prostaglandin synthesis (Hardman et al.,
2001) or long-term loss of urine-concentrating ability arising
through papillary necrosis and interstitial nephritis, which are typical of
analgesic nephropathy (Henrich,
1998).
We could not distinguish between these two possible mechanisms in the
previous study (Ahmed et al.,
2003b), because animals continued to receive paracetamol in their
drinking water up until the time that renal function was assessed. Paracetamol
has a plasma half-life of 2 to 4 h, being inactivated in the liver
(Hardman et al., 2001), and
its excretion rate is markedly reduced by renal impairment
(Prescott et al., 1989), so it
is highly likely that paracetamol remained in the circulation of these animals
during the measurement of their renal function. Consequently, we may have
observed acute paracetamol-mediated effects on chloroquine's actions on the
kidney in addition to those attributable to analgesic nephropathy alone.
Accordingly, the aim of this study was to determine the renal action of acute
paracetamol infusion and its influence on chloroquine-mediated changes in
renal function in the absence of long-term paracetamol-induced changes in the
kidney. This was achieved by assessing renal function in previously untreated
rats receiving acute infusion of either paracetamol or chloroquine, or a
combination of the two drugs.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Animal Preparation. Male Sprague-Dawley rats were purchased from
Charles River (Margate, Kent, UK) and were held in the School of Biological
Sciences where they had free access to food (Beekay Rat and Mouse Standard
Diet; Bantin and Kingman Ltd., Hull, UK) and water, with a 12-h light and 12-h
dark cycle before experimentation. The weight of animals at renal function
study was between 330 and 340 g. Animals were anesthetized with intraval (100
mg kg–1 b.wt., thiopentone sodium BP;
Rhone-Poulenc Rorer Limited, Nenagh, Co Tipperary, Ireland) and transferred to
a hot-plate that maintained body temperature, monitored by a rectal probe, at
37°C throughout the experiment. Cannulae were inserted into an external
jugular vein, carotid artery, and the bladder and a tracheotomy was performed,
as described previously (Ahmed et al.,
2003a,b).
The Servo-Controlled Fluid Replacement System. Euvolemic fluid
replacement of spontaneous urine output was achieved using a servo-controlled
fluid replacement system, as described previously (Ahmed et al.,
2003a,b).
Briefly, urine flow rate, determined gravimetrically, is transmitted to an
adjustable pump via a computer. A program developed at the University of
Manchester (Burgess et al.,
1993) allows the infusion rate of the pump to be automatically
adjusted to precisely replace intravenously the volume of fluid lost as urine.
Clearance marker ([3H]inulin in 2.5% dextrose, 6 µCi
h–1; Amersham Biosciences UK, Ltd., Little
Chalfont, Buckinghamshire, UK) is delivered via a second, slow, constant
infusion pump (1 ml h–1).
Experimental Protocol. After surgery, a bolus dose of
[3H]inulin (6 µCi) was injected via the venous cannula and
servo-infusion replacement initiated. All animals were allowed a 3-h
equilibration period, after which animals were assigned to vehicle (n
= 6), paracetamol (n = 6), chloroquine (n = 6), or
paracetamol/chloroquine (n = 6) groups for the remaining 3 h of the
experiment. All rats received 2.5% dextrose replacement for a 1-h control
period. The vehicle animals continued to receive 2.5% dextrose for the
remaining 2 h of the experiment. In the chloroquine-treated group, infusion of
chloroquine (0.04 mg h–1 chloroquine diphosphate;
Sigma-Aldrich, Poole, Dorset, UK; previously shown in our hands to affect
renal function in the anesthetized rat; Ahmed et al.,
2003a,b)
was started via the constant infusion pump for 1 h, after which the infusate
was switched to 2.5% dextrose for the final hour of the experiment.
In the paracetamol-treated group, paracetamol was administered initially as
a loading dose of 210 mg kg–1 immediately after
the control hour, followed by a continuous infusion at 110 mg
kg–1 h–1 for 2 h
(Jang et al., 1994;
Sigma-Aldrich). In the final group, a loading dose of paracetamol was given
after the control hour after which combined paracetamol and chloroquine
infusion commenced for an hour. Chloroquine infusion ceased after 1 h and rats
continued to receive paracetamol for the final hour. Urine samples were
collected every 10 min after the equilibration period, and blood samples were
collected at 0.5, 1.5, and 2.5 h postequilibration. Blood samples (0.6 ml)
were collected from the carotid artery, and a similar volume of dextrose
solution was replaced. Plasma was separated by centrifugation and stored at
4°C before analysis.
Analysis. Urine and plasma sodium concentrations were measured by flame photometry (Corning 480; Corning Ltd., Halstead, Essex, UK) and osmolality by freezing point depression (Roebling osmometer; LH Roebling, Berlin, Germany). [3H]Inulin was determined using a 1900CA Tri-Carb liquid scintillation analyzer (Canberra Industries, Meriden, CT) beta-counter.
Statistical Analysis. Data are presented as the mean ± S.E.M. Statistical analysis was performed using SPSS for Windows (standard version 10.1.0; SPSS UK Ltd., Woking, Surrey, UK). Comparisons between groups over time were by repeated measures ANOVA, and comparisons within control, treatment, or recovery periods were by ANOVA followed by Student-Newman-Keuls test. Significance was ascribed at the 5% level.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Mean arterial blood pressure remained stable over the course of the whole experiment and did not differ between groups (vehicle, 126 ± 3; chloroquine, 130 ± 4; paracetamol, 129 ± 3; chloroquine/paracetamol, 125 ± 2 mm Hg).
There were no differences in glomerular filtration rate (Fig. 2; ANOVA 1st h, F3,23 = 0.49, p = 0.69), sodium excretion rate (Fig. 3; F3,23 = 1.73, p = 0.19) nor urine osmolality (Fig. 4; F3,23 = 0.25, p = 0.86) during the initial postequilibration control hour between the four groups. Thus, for ease of comparison, in subsequent graphs the mean values are presented for the control, postequilibration hour (1st h), the hour of drug treatment (2nd h), and the recovery hour (3rd h).
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Glomerular Filtration Rate. Chloroquine infusion resulted in a significant increase in GFR by comparison with vehicle-infused rats (Fig. 2) over both the 2nd h (ANOVA 2nd h, F3,23 = 7.55, p = 0.001; post hoc SNK test vehicle versus chloroquine p < 0.01) and the 3rd, recovery hour (ANOVA 3rd hour, F3,23 = 8.48, p = 0.001; vehicle versus chloroquine p < 0.001). Paracetamol alone had no effect on GFR. When chloroquine and paracetamol were coinfused, GFR remained at a rate comparable with vehicle-infused rats over the 2nd hour (chloroquine versus chloroquine/paracetamol p < 0.05). There was an increase in GFR over the 3rd hour (vehicle versus chloroquine/paracetamol p < 0.05), but not to the same extent as that seen with chloroquine alone (chloroquine versus chloroquine/paracetamol p < 0.05).
Sodium Excretion. Urinary sodium excretion is depicted in Fig. 3. Chloroquine infusion resulted in a marked increase in sodium excretion by comparison with the vehicle group over both hours (ANOVA 2nd h, F3,23 = 18.3, p < 0.001, post hoc SNK test vehicle versus chloroquine p < 0.001; ANOVA 3rd h, F3,23 = 47.1, p < 0.001; vehicle versus chloroquine p < 0.001). In contrast, paracetamol infusion resulted in a significant fall in urinary sodium output compared with vehicle infused rats over both the 2nd (vehicle versus paracetamol p < 0.05) and 3rd h (p < 0.05). When chloroquine and paracetamol were coinfused, the sodium excretion rate was comparable with that seen with paracetamol alone. For both hours, the sodium excretion rate of rats receiving a combination of chloroquine and paracetamol was significantly lower than that of vehicle-infused rats (2nd and 3rd h, vehicle versus chloroquine/paracetamol p < 0.05) and chloroquine-infused rats (2nd and 3rd h, chloroquine/paracetamol p < 0.05).
Urine Osmolality. Urine osmolality is shown in Fig. 4 as an indication of urine-concentrating ability. There was a significant (F2,15 = 31.5, p < 0.001) decline in urine osmolality over time in vehicle-treated animals reflecting the concomitant increase in urine flow rate (Fig. 1) and lack of sodium load in the infusate. Despite this decrease in vehicle-treated rats over time, the urine osmolality of rats infused with chloroquine was significantly lower than that of vehicle infused rats over both the 2nd (vehicle versus chloroquine p < 0.05) and 3rd h (p < 0.05). Paracetamol infusion did not alter urine osmolality compared with vehicle-treated rats. However, when chloroquine and paracetamol were coinfused, urine osmolality was significantly higher than that of vehicle-infused and chloroquine-infused rats over both hours (2nd h vehicle versus chloroquine/paracetamol p < 0.05, chloroquine versus chloroquine/paracetamol p < 0.01; 3rd h vehicle versus chloroquine/paracetamol p < 0.05, chloroquine versus chloroquine/paracetamol p < 0.05).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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) and
extends our observations of the effects of paracetamol on renal excretion of
salt and water (Ahmed et al.,
2003b). It also demonstrates that the modifying effect of
paracetamol on chloroquine's renal actions depends on the length of prior
exposure to paracetamol.
In our previous study (Ahmed et al.,
2003b) we reported that paracetamol administration at 500 mg
kg–1 b.wt. day–1 for
30 days induced a subclinical level of analgesic nephropathy that was typified
by a reduction in GFR, sodium excretion, and urine osmolality coupled with a
somewhat higher urine flow rate. In the present study, paracetamol was
administered to previously untreated rats to assess its short-term actions on
renal function in undamaged kidneys. The infusion was maintained over 2 h
because the half-life of paracetamol after intravenous administration has been
shown to be <30 min (Prescott,
1980; Schlondorff,
1993). Under these conditions, paracetamol infusion was associated
with only a modest reduction in GFR, a significant fall in sodium excretion,
and no change in urine osmolality or urine flow rate by comparison with
vehicle-infused control rats. The most notable difference between the two
treatment regimes was in urine osmolality [acute paracetamol (this study),
n = 6, 334.0 ± 34.5 versus chronic paracetamol
(Ahmed et al., 2003b),
n = 6, 135.4 ± 10.8 mOsM kg
H2O–1, p < 0.01],
indicating that rats receiving paracetamol for 30 days had impaired urine
concentrating ability, which is a typical feature of analgesic nephropathy
(Henrich, 1998).
Paracetamol is a rapid, reversible, noncompetitive inhibitor of
cyclooxygenase (Hardman et al.,
2001). It has been shown to decrease both renal blood flow and GFR
in the dog in vivo (Colletti et al.,
1999) and to decrease GFR in the isolated perfused rat kidney
(Trumper et al., 1998). Hence,
the modest reduction in GFR with paracetamol observed over the 2nd hour of the
present study is in accord with the previously reported actions of
paracetamol. Chronic paracetamol treatment resulted in a marked reduction in
GFR (Ahmed et al., 2003b),
presumably reflecting greater or more sustained influence of paracetamol on
renal function.
There were also differences in the urine flow rate between the two studies.
Urine flow in rats receiving chronic paracetamol was double that of control,
untreated rats (Ahmed et al.,
2003b), whereas in the current study, urine flow after acute
paracetamol was not significantly different from that of vehicle-infused rats.
This probably reflects the influence of papillary damage and a reduction in
urinary concentrating ability after long-term paracetamol administration.
Indeed, short-term infusion of paracetamol might be expected to result in a
reduction in urine flow rate because acute administration of NSAIDs is
associated with an elevation in vasopressin secretion
(Wilkinson and Kasting, 1993;
Walker et al., 1994). Although
we did not measure plasma vasopressin in this study, it is likely that urine
output after acute paracetamol infusion was moderated by an increase in
circulating vasopressin concentration.
One possible explanation for the antinatriuretic effect of acute and
chronic (Ahmed et al., 2003b)
paracetamol administration is the inhibition of renal prostaglandin synthesis.
Prostaglandin E2 infusion has been shown to increase sodium
excretion (Villa et al., 1997)
and inhibit active transport of NaCl in the thick ascending limb and cortical
collecting duct of isolated perfused nephrons
(Stokes, 1979;
Kokko, 1981). The threshold
dose of paracetamol required to inhibit sodium excretion is also the same as
that which inhibits prostaglandin synthesis
(Feldman et al., 1978). Thus,
in both studies it is possible that paracetamol may have altered renal tubular
sodium handling by inhibiting prostaglandin synthesis. However, in future
studies measurements of renal prostaglandin excretion are required to confirm
this suggestion.
The renal effects of coadministered paracetamol and chloroquine depend, in
part, on alterations in their pharmacokinetics when the two drugs are infused
at the same time. Chloroquine and paracetamol are both metabolized through the
P450 pathway by the liver (Raucy et al.,
1989; Lancaster et al.,
1990) and thus the presence of one drug can affect the clearance
rate of the other. Hence, prior paracetamol treatment has been shown to
increase the maximum serum concentration of chloroquine after a single oral
dose in humans and also increased the area under the chloroquine concentration
curve (Raina et al., 1993). In
the converse situation, when paracetamol was administered to volunteers
already treated with chloroquine, chloroquine increased the maximal plasma
paracetamol concentration achieved
(Adjepon-Yamoah et al.,
1986).
In the current study, coadministration of paracetamol with chloroquine
completely blocked the increase in urine flow rate seen with chloroquine
administration alone. A similar pattern of response was observed when
chloroquine was infused into rats after chronic paracetamol treatment
(Ahmed et al., 2003b). This
suggests that the influence of paracetamol on chloroquine-mediated diuresis
may arise through a mechanism other than long-term damage to the renal
concentrating mechanism. We have previously suggested that chloroquine
stimulates a diuresis in anesthetized, euvolemic rats by a combination of
nitric oxide-induced cGMP generation and prostaglandin synthesis
(Ahmed et al., 2003b).
Together, these could act to inhibit the increase in medullary collecting duct
cAMP generation that is expected to arise after a chloroquine-induced increase
in plasma vasopressin concentration
(Musabayane et al., 1996;
Ahmed et al., 2003a). However,
in the presence of paracetamol, a combination of higher circulating
vasopressin levels (Ahmed et al.,
2003b) and a predicted decreased in prostaglandin synthesis may
allow sufficient cAMP generation to activate aquaporin 2 insertion and
facilitate water reabsorption in the collecting duct. Again, further study is
required to establish the role of renal prostaglandins in this suggested
mechanism.
Combined infusion of paracetamol and chloroquine attenuated, but did not
completely abolish, the marked increase in GFR observed after infusion of
chloroquine alone. A similar response was observed after infusion of
chloroquine into rats after chronic paracetamol treatment
(Ahmed et al., 2003b).
Chloroquine seems to induce renal nitric oxide synthesis (Ahmed et al.,
2003a,b).
Nitric oxide activates both constitutive and inducible cyclooxygenase,
resulting in an increase in vasodilatory prostaglandins
(Salvemini et al., 1993).
Thus, together, nitric oxide and prostaglandins might be expected to cause
vasodilatation and an increase in GFR. If paracetamol inhibits cyclooxygenase
(Hardman et al., 2001), this
vasodilatory tone will be diminished, resulting in an attenuated GFR response
to chloroquine.
The inhibitory effect of acute paracetamol and chloroquine infusion on
sodium excretion differed from the natriuresis observed after chloroquine
infusion after chronic paracetamol treatment
(Ahmed et al., 2003b). This
does not seem to arise through differences in the filtered load of sodium,
because GFR was comparable in the two experimental groups. Rather, this
probably reflects the loss of urinary concentrating ability typical of
analgesic nephropathy after chronic NSAID administration. Against such a
background, the natriuretic effect of chloroquine-induced nitric oxide
dominates by inhibiting proximal tubule sodium reabsorption
(Eitle et al., 1998). When
chloroquine is coinfused with paracetamol in an animal with a fully functional
kidney, the increased delivery of sodium from the proximal tubule to the
distal nephron seems to be completely reabsorbed. The site of action is not
clear from these data, but could involve the thick ascending limb, because
prostaglandin E2 inhibits sodium reabsorption in this segment
(Kaojarern et al., 1983), or
it may reflect a change in tubuloglomerular balance.
In summary, acute paracetamol administration reduced renal sodium
excretion, but had no effect on urine flow rate, GFR, or urine osmolality.
This contrasts with our previous observations of the effects of chronic
paracetamol treatment, which was associated with a reduction in GFR, sodium
excretion, and urine osmolality and a tendency toward higher urine output
(Ahmed et al., 2003b). These
differences reflect renal responses that may be mediated, at least in part, by
prostaglandins or other humoral factors, and hence can occur after both acute
and long-term paracetamol treatment, and those that arise as a result of
damage to the renal concentrating mechanism and only occur after long-term
paracetamol treatment. Modification of chloroquine-induced changes in renal
function could also reflect mechanisms involving prostaglandin inhibition or
urine concentration deficit. Hence, when coadministered with chloroquine,
acute paracetamol infusion inhibited the diuretic and natriuretic effects of
chloroquine and restored GFR to levels comparable with the vehicle-infused
controls. Chronic paracetamol treatment was similarly effective in blocking
the increase in GFR and diuresis associated with chloroquine infusion, but
failed to inhibit the natriuresis (Ahmed et
al., 2003b). These data suggest that the effects of paracetamol on
basal and chloroquine-mediated renal function depend on the length of prior
exposure to the drug and thus the presence or absence of analgesic
nephropathy.
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Footnotes |
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ABBREVIATIONS: GFR, glomerular filtration rate; NSAID, nonsteroidal anti-inflammatory drug; ANOVA, analysis of variance; SNK, Student-Newman-Keuls.
Address correspondence to: Dr. Nick Ashton, School of Biological Sciences, University of Manchester, G38 Stopford Bldg., Oxford Rd., Manchester M13 9PT, UK. E-mail: nick.ashton{at}man.ac.uk
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