Department of Physiology, School of Medicine, University of Murcia, 30100 Murcia, Spain
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ABSTRACT |
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The objective of this
study was to examine the role of cylcooxygenase (COX)-2-derived
prostaglandins (PG) in modulating the renal hemodynamic effects of
norepinephrine (NE) during low or normal sodium intake. The
relative contribution of each COX isoform in producing the PG that
attenuate the renal NE effects during normal sodium intake was also
evaluated. The renal response to three doses of NE (50, 100, and 250 ng · kg1 · min
1) was
evaluated in anesthetized dogs pretreated with vehicle, a selective
COX-2 inhibitor (nimesulide), or a nonselective COX inhibitor
(meclofenamate). Intrarenal infusion of the two lower doses of NE in
vehicle-pretreated dogs with normal sodium intake (n = 8) elicited an increase in renal vascular resistance (RVR; 21 and 34%)
without inducing changes in glomerular filtration rate (GFR). The
highest dose of NE in this group induced a further increment in RVR
(113%) and a decrease in GFR (33%). Pretreatment with nimesulide in
dogs with normal sodium intake (n = 7) did not modify
the NE-induced increments in RVR but enhanced the decreases in GFR
induced by the three NE doses (12, 26, and 64%). The renal hemodynamic
response to NE in meclofenamate-pretreated dogs with normal sodium
intake (n = 7) was similar to that found in dogs pretreated with nimesulide. Infusion of the lowest dose of NE to
vehicle-pretreated dogs with low sodium intake (n = 6)
did not modify GFR and elicited an increase in RVR (42%). Infusion of
the second and third doses of NE led to a decrease in GFR (35 and 91%)
and a rise in RVR (82 and 587%). Infusion of the first two doses of NE
in nimesulide-pretreated dogs with low sodium intake (n = 5) induced a fall in GFR (64 and 92%) and an increase in RVR (174 and 2,293%) that were greater (P < 0.05) than
those induced by NE in vehicle-pretreated dogs. The elevation in the urinary excretion rates of PGE2 and
6-keto-PGF1
elicited by NE was prevented in the
nimesulide-pretreated dogs. Our results show that COX-2
inhibition potentiates the renal hemodynamic effects of NE and propose
that the PG involved in modulating them are mainly derived from COX-2 activity.
renal function; glomerular filtration rate; renal vascular resistance; prostaglandins; cyclooxygenase-2
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INTRODUCTION |
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IT IS WELL KNOWN THAT ENDOGENOUS prostaglandins (PG) play an important role in regulating renal function when vasoconstrictor levels are elevated (1-3, 6, 14, 15, 18, 22). This notion is supported by studies showing that norepinephrine (NE) infusion induces an increment in renal synthesis of PG (5, 15) and that the renal vasoconstriction induced by NE is significantly potentiated when synthesis of PG is reduced (1, 2, 15). Finally, it has been reported that PGI2 infusion reduces the renal vasoconstriction elicited by NE (3, 14).
Several studies have shown that both cyclooxygenase (COX) isoforms are constitutively expressed in the kidney and that the intrarenal localization of COX-1 and COX-2 is different (9, 10, 16, 28). It has also been reported that the importance of each COX isoform in regulating renal hemodynamics is dependent on the level of several hormones (10, 13, 19, 23, 24). Although, as already mentioned, a great deal of evidence indicates that endogenous PG attenuate the renal vasoconstriction induced by NE, the relative contribution of both COX isoforms in producing the PG that modulate the NE effects on renal blood flow (RBF) and glomerular filtration rate (GFR) is unknown thus far. The hypothesis that COX-2-derived metabolites may protect the renal vasculature from the NE-induced vasoconstriction is supported by the results obtained in an in vitro experiment (13).
The main purpose of this study was to evaluate the contribution of COX-2-derived metabolites in modulating the renal vasoconstriction induced by NE during low or normal sodium intake. To accomplish this objective, NE was infused at three doses into the renal artery of dogs with normal or low sodium intake, the animals having been pretreated with vehicle or a selective COX-2 inhibitor (nimesulide). Because COX-2 expression in the renal cortex is enhanced when sodium intake is low (10), the hypothesis was that COX-2 inhibition would potentiate the renal vasoconstriction elicited by NE more when sodium intake is low than when sodium intake is normal. In dogs with normal sodium intake, the renal effects elicited by NE when both COX isoforms are inhibited by meclofenamate versus when only COX-2 is inhibited by nimesulide were compared. The objective was to evaluate the contribution of each COX isoform in producing the PG that modulate the renal hemodynamic effects of NE.
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METHODS |
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Experiments were performed in mongrel dogs of either sex (17-26 kg) that had free access to tap water. Protocols were designed according to the Guiding Principles in the Care and Use of Animals approved by the Council of the American Physiological Society. Six days before the experiments, the dogs were housed in individual metabolic cages and fed a low- or normal-sodium diet. The low-sodium diet provided 5-7 mmol sodium/day. On the fifth and sixth days before the experiments, diuretics were given to dogs on the sodium-deficient diet (Hill Pet Products). Diuretics were administered to ensure the dogs were volume depleted (26).
Surgical preparation was performed in anesthetized dogs (30 mg/kg pentobarbital sodium), as previously described (18, 22-26). Catheters were placed in the femoral artery for measurement of mean arterial pressure (MAP) and in the femoral vein for infusion of inulin and nimesulide or meclofenamate. Inulin was dissolved in isotonic saline (0.9% NaCl) for experiments performed in dogs with normal sodium intake and dissolved in a glucose solution (5%) for experiments performed in dogs with low sodium intake. The right renal artery was fitted with noncannulating electromagnetic flow probes, and the probes were connected to a flowmeter. Distal to the flow probe, a curved 23-gauge needle attached to polyethylene tubing was inserted into the right renal artery and connected to a peristaltic pump for infusion of saline or NE. A 45-min stabilization period was allowed before experimental maneuvers were begun.
Experimental Groups
Group 1 (n = 8).
The protocol was performed in dogs with normal sodium intake. Two
15-min control clearance collections were followed by intrarenal infusions of NE at rates of 50, 100, and 250 ng · kg1 · min
1. Each NE
dose was infused over 35 min, and one clearance was obtained during the
last 20 min of each infusion.
Group 2 (n = 7).
In dogs with normal sodium intake, the experimental protocol performed
was similar to that described for group 1, with the difference that nimesulide was infused as a bolus (0.75 mg/kg) and then
continuously (5 µg · kg1 · min
1) for the
duration of the experiment. The two 15-min control clearances were
obtained 45 min after the continuous nimesulide infusion was initiated.
The dose of nimesulide used reduces urinary PGE2 excretion
by >40% and does not affect the platelet aggregation induced by
arachidonic acid in platelet-rich plasma (23). In dogs
with normal sodium intake, this dose of nimesulide does not alter renal
hemodynamics and reduced urinary sodium and water excretion (19,
23, 24).
Group 3 (n = 7).
The experimental protocol for dogs with normal sodium intake was
similar to that described for group 1, with the difference that meclofenamate was infused as a bolus (3 mg/kg) and then
continuously (10 µg · kg1 · min
1) for the
duration of the experiment. The two 15-min control clearances were
obtained 45 min after meclofenamate infusion was begun. The dose of
meclofenamate used induces significant renal vasoconstriction, is
effective in reducing urinary PGE2 excretion by >90%, and
prevents the platelet aggregation induced by arachidonic acid in
platelet-rich plasma (19, 23, 24).
Group 4 (n = 6). The experimental protocol was similar to that accomplished in group 1, the only difference being that it was performed in dogs with low sodium intake.
Group 5 (n = 5).
The protocol was performed in dogs with low sodium intake. Nimesulide
was infused at the same dose used in group 2. After the two
15-min control clearances, each NE dose (50, 100, and 250 ng · kg1 · min
1) was
infused over 35 min, and one clearance was obtained during the last 20 min of each infusion. When dogs with low sodium intake were infused,
the dose of nimesulide used elicits a significant increase in renal
vascular resistance (RVR) with no changes in GFR (23).
Analytic Methods
Renal clearances were taken during each experimental period to determine GFR, sodium excretion (UNaV), and urine flow rate (UVol). Urine samples were obtained from groups 4 and 5 to evaluate urinary excretion rates for PGE2, 6-keto-PGF1Statistical Analysis
The data for the two clearances obtained during the control period were averaged for statistical comparison because the fluid and solute excretions were measured in steady-state conditions. Data are expressed as means ± SE. For each group, significant differences in values for each period was evaluated using ANOVA for repeated measures and Fisher's test. Significant differences among groups during one experimental period were calculated with the use of ANOVA and Fisher's test. ![]() |
RESULTS |
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Group 1
MAP increased progressively (P < 0.05) from a control value of 132 ± 6 to 137 ± 6, 140 ± 6, and 145 ± 6 mmHg, respectively, during the intrarenal infusion of the three doses of NE (50, 100 and 250 ng · kg
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Group 2
In nimesulide-pretreated dogs with normal sodium intake, the intrarenal infusion of the three NE doses caused a progressive rise in MAP (P < 0.05) that was similar to that found in the control group. Renal hemodynamic changes in this group are depicted in Fig. 2. Contrary to what was found in vehicle-pretreated dogs, GFR decreased (P < 0.05) during infusion of the first (33 ± 3 ml/min) and second (28 ± 3 ml/min) doses of NE in dogs with normal sodium intake in which COX-2 activity was reduced with nimesulide (Fig. 2). GFR during the control period was 39 ± 4 ml/min. The fall in GFR in this group elicited by the highest dose of NE (to 13 ± 2 ml/min) was also greater (P < 0.05) (Fig. 2) than that found in the control group (Fig. 1). As shown in Fig. 2, in nimesulide-pretreated dogs NE infusion induced a decrease (P < 0.05) in RBF that was similar to that elicited in the control group (Fig. 1). FF decreased (P < 0.05) during the administration of the highest NE dose (0.26 ± 0.03 vs. 0.37 ± 0.03 in the control period). RVR increased (P < 0.05) in nimesulide-pretreated dogs during infusion of the first, second, and third doses of NE (0.85 ± 0.05, 0.92 ± 0.05, and 1.76 ± 0.26 mmHg · ml
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Group 3
In meclofenamate-pretreated dogs, intrarenal NE infusion elicited an increase in MAP and RVR and a decrease in RBF (Fig. 3) that were not significantly different from those induced by NE in the other two group of dogs with normal sodium intake (Figs. 1 and 2). NE infusion into meclofenamate-pretreated dogs also induced a dose-dependent fall in GFR (Fig. 3) that was similar to that found in nimesulide-pretreated dogs (Fig. 2) and greater (P < 0.05) than that elicited by NE in the control group (Fig. 1). GFR decreased from a basal value of 41 ± 4 to 33 ± 4, 27 ± 2, and 14 ± 3 ml/min after the three respective NE infusions. RVR increased progressively from a basal value of 0.76 ± 0.03 to 0.88 ± 0.03, 1.18 ± 0.17, and 2.66 ± 0.76 mmHg · ml
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Group 4
For control dogs with low sodium intake, intrarenal infusion of the three NE doses increased (P < 0.05) MAP progressively from a basal value of 129 ± 3 mmHg to 142 ± 4, 148 ± 4, and 160 ± 4 mmHg, respectively. These increments in MAP were greater than those elicited by NE in the control group with normal sodium intake. GFR was not significantly modified in this group (Fig. 4) during infusion of the first NE dose (29 ± 2 ml/min vs. basal value of 34 ± 2 ml/min) and decreased (P < 0.05) during the infusion of the second (22 ± 2 ml/min) and third (3 ± 1 ml/min) NE doses. RVR increased (P < 0.05) from 0.67 ± 0.05 to 0.95 ± 0.08, 1.22 ± 0.16, and 4.60 ± 0.67 mmHg · ml
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Changes in urinary excretion rates of PGE2,
6-keto-PGF1, and 11-dehydro-TXB2 during
intrarenal infusion of the first and second NE doses are shown in Fig.
5. It can be observed that PGE2 excretion increased (P < 0.05) from
3.76 ± 0.58 to 8.06 ± 0.64 and 8.47 ± 0.63 ng/min,
respectively, and that 6-keto-PGF1
excretion increased
from 2.56 ± 0.89 to 8.98 ± 2.89 and 9.89 ± 2.27 ng/min, respectively. In contrast to these increments in PGE2 and 6-keto-PGF1
, the excretion rate of
the TxB2 metabolite did not change significantly during NE
infusion (Fig. 5).
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Group 5
With intrarenal NE infusion, dogs with low sodium intake pretreated with nimesulide elicited a progressive increment in MAP that was similar to that found in vehicle-pretreated dogs with low sodium intake. One important difference in this group (Fig. 6, Table 2) with respect to the other four groups is that both RBF and UVol decreased to undetectable levels during the infusion of the highest dose of NE. The second dose of NE already decreased (P < 0.05) GFR and RBF to 2.5 ± 1.3 and 16 ± 7 ml/min, respectively, and increased (P < 0.05) RVR to 21.3 ± 5.6 mmHg · ml
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DISCUSSION |
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The results of this study suggest that NE enhances the production of COX-2-derived PG (PGE2 and PGI2) and that these PG play an important role in modulating the renal vasoconstriction elicited by NE. The modulation by these COX-2-derived metabolites of NE-induced vasoconstriction is more evident when sodium intake is low than when sodium intake is normal. It was also found in dogs with normal sodium intake that the enhanced NE-induced renal vasoconstriction is similar in dogs pretreated with a nonselective COX inhibitor and in those pretreated with a selective COX-2 inhibitor. These results are interpreted as suggesting that the PG involved in the attenuation of the renal vasoconstriction induced by NE are mainly derived from COX-2 activity.
As previously described (5), the increase in RVR elicited by NE in our study is proportional to the rise in NE levels. The intrarenal infusion of the two lower doses of NE to dogs with normal sodium intake led to a progressive decrease in RBF and no significant changes in GFR. Our results are consistent with studies showing that there are frequencies of renal nerve stimulation that decreased RBF and kept GFR unchanged (5). With the consideration that NE increases both pre- and postglomerular resistance (5, 17), our results suggest that the infusion of the two lower doses of NE to dogs with normal sodium intake elevates the efferent more than the afferent arteriolar resistance. This greater effect of NE on postglomerular resistance seems to occur only when sodium intake is normal, because it was found in dogs with low sodium intake that GFR decreased in response to the intrarenal infusion of the three doses of NE. The decrease in GFR elicited by NE seems to be due to a combination of an increase in afferent arteriolar resistance and a decrease in the glomerular capillary ultrafiltration coefficient (Kf) (5). The marked fall in Kf caused by renal sympathetic nerve stimulation is at least partly related to decreased glomerular capillary surface area (17).
As occurs with other vasoconstrictors, such as angiotensin II (1,
3, 14, 18), effects of NE on renal microcirculation are
modulated by nitric oxide (NO) and PG (1-3, 6, 8, 14, 15,
20). The role of PG in attenuating the renal vasoconstriction induced by NE has been proposed in studies showing that 1)
NE increases the production of PG in the kidney (6, 15);
2) COX inhibition leads to a marked potentiation of
NE-induced renal vasoconstriction (1, 2, 15); and
3) PG infusion attenuates the renal vasoconstriction
elicited by NE (3, 14). Some results reported in the
aforementioned previous studies have been confirmed in our study,
because we have found that intrarenal infusion of NE enhances the
urinary excretion of PGE2 and 6-keto-PGF1 and that the renal hemodynamic effects of NE are potentiated by the
infusion of a nonselective COX inhibitor. With the consideration that
renal PG are produced by both COX isoforms, which are constitutively expressed in the renal cortex (9, 10, 16, 28), the
possibility exists that only one or both COX isoforms are involved in
the production of those PG that modulate the renal vasoconstrictor effects of NE. To evaluate the relative contribution of both COX isoforms in the synthesis of the PG that attenuate the renal
hemodynamic effects of NE during normal sodium intake, we have compared
the renal changes elicited by three doses of NE in dogs pretreated with
saline, a selective COX-2 inhibitor, and a nonselective COX inhibitor.
We have also examined whether COX-2-derived metabolites play a more
important role in modulating the renal hemodynamic effects of NE when
sodium intake is low than when sodium intake is normal. The hypothesis
was that COX-2 metabolites would attenuate the renal vasoconstriction
induced by NE more when sodium intake is low because COX-2 expression
in the renal cortex is greater when sodium intake is low than when
sodium intake is normal (10).
The results of the present study clearly demonstrate that infusion of a
selective COX-2 inhibitor prevents the elevation in the urinary
excretion rates of PGE2 and 6-keto-PGF1
elicited by NE and significantly enhanced the NE effect on GFR, two
novel findings that have not been reported so far to our knowledge. As
expected, the greater renal vasoconstriction induced by NE in dogs
pretreated with the COX-2 inhibitor was more evident in dogs with low
sodium intake than in those with normal sodium intake. It has also been
found in our study that inhibition of COX-2 only or inhibition of both
COX isoforms enhances to a similar extent the effect of NE on GFR. The
renal hemodynamic effects of NE during normal sodium intake are similar
to those found in response to renal nerve stimulation in experiments in
which both COX isoforms were inhibited (5, 30). Our
results are consistent with those obtained in in vitro studies showing
that PG seem to be more effective in reducing the vasoconstrictor
effect induced by NE on the afferent than on the efferent arteriole
(5, 7). Taken together with the results obtained in
micropuncture studies (5, 21) and in studies evaluating
the expression of COX-2 in the renal cortex (10, 28), the
present findings suggest that COX-2, present in and around the macula
densa cells, exerts an important counteracting modulatory influence of
the vasoconstriction induced by NE on the afferent arteriole and/or
mesangial cells. In a micropuncture study, Pelayo (21)
proposed that the larger decrease in GFR induced by renal nerve
stimulation during COX inhibition (with indomethacin) is secondary to a
greater constriction of the afferent arteriole and to a significant
decline in Kf.
The notion that COX-2-derived metabolites attenuate the afferent arteriolar vasoconstrictor effect of NE is supported by the results reported by Imig and Deichmann (13) in one study performed in an in vitro perfused rat juxtamedullary nephron preparation. The afore-mentioned authors found that the afferent arteriolar vasoconstrictor response to NE was enhanced similarly by a nonselective and a selective COX-2 inhibitor. The cellular signaling pathways by which NE regulates COX-2 activity remain a task for future research, but it can be proposed that the NE-induced activation of COX-2 may depend primarily on both extra- and intracellular Ca2+ and calmodulin (4). The involvement of COX-2 in modulating renal vasoconstriction is not specific for NE because other vasoconstrictors, such as endothelin, also increase COX-2-dependent PGE2 production in mesangial cells (11). Intrarenal COX-2 activity is enhanced not only in response to vasoconstrictors, because inhibition of the renin-angiotensin system also upregulates COX-2 expression in the macula densa (29). The decrease in RVR elicited by bradykinin also seems to be mediated by COX-2-derived metabolites (24).
As previously mentioned, NO plays an important role in mediating the renal vascular response to NE (8, 20). It has also been proposed that NO enhances COX-2 activity under different experimental conditions (12, 24, 27). A possibility that requires further investigation is that NE increases NO synthase activity and that the NO produced induces a rise in COX-2 activity. The NO- and COX-2 derived metabolites synthesized as a consequence of the increased activity of both enzymes would then modulate the renal vasoconstrictor effects elicited by NE.
Intrarenal NE infusion induced not only renal vasoconstriction but also a decrease in renal excretory ability. The decrease in sodium and water excretion could be secondary to the renal hemodynamic changes and also to a direct tubular effect (5). However, and contrary to the effect on renal hemodynamics, PG do not seem to modulate the effect of NE on sodium and water reabsorption because COX inhibition does not significantly modify the NE-induced changes in renal excretory ability.
In summary, our results suggest that COX-2-derived metabolites play an important role in counteracting the renal vasoconstriction elicited by NE and that the attenuation of the renal hemodynamic effects of NE by these metabolites is more important when sodium intake is low than when sodium intake is normal. This hypothesis is supported by results showing that the NE-induced renal hemodynamic changes are significantly enhanced when COX-2 activity is inhibited. Taken together with the results obtained in in vitro studies, our results suggest that COX-2 inhibition enhances the effect of NE on renal hemodynamics by increasing vasoconstriction of the afferent arteriole and by decreasing Kf.
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ACKNOWLEDGEMENTS |
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This study was supported by grants from the Fondo de Investigaciones Sanitarias of Spain (FIS; 98/1309 and 99/1024). M. T. Llinás was supported by a grant from University of Murcia. F. Rodríguez and F. Roig were supported by a grant from the FIS (98/1309). Nimesulide was kindly provided by Roche Labs.
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FOOTNOTES |
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Address for reprint requests and other correspondence: F. Javier Salazar, Departamento de Fisiología, Facultad de Medicina. 30100 Murcia, Spain (E-mail: salazar{at}um.es).
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. Section 1734 solely to indicate this fact.
Received 17 August 2000; accepted in final form 10 July 2001.
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