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1 Department of Medical Physiology, University of Copenhagen, DK-2200; and 2 Department of Physiology and Pharmacology, University of Southern Denmark, DK-5000 Odense, Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The responses to
AT1-receptor blockade (candesartan 1 mg/kg) and to
concomitant volume expansion (saline 35 ml/kg for 90 min) with and
without nitric oxide synthase (NOS) inhibition
(NG-nitro-L-arginine methyl ester 30 µg · kg
1 · min1) were
investigated in separate experiments in normal dogs.
AT1 blockade decreased arterial pressure (106 ± 4 to 96 ± 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 ± 3 to 116 ± 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT1 blockade and NOS inhibition (21 ± 4 mmHg). Volume expansion during AT1 blockade elicited marked natriuresis (26 ± 11 to 274 ± 55 µmol/min) that was severely reduced by concomitant NOS inhibition (10 ± 3 to 45 ± 11 µmol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 ± 1 to 23 ± 7 µmol/min). Volume expansion during AT1 blockade increased GFR (+30%), less so during combined AT1 blockade and NOS inhibition (+13%), but it did not increase GFR significantly (P = 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with AT1 blockade and doubled with NOS inhibition (paired t-test, P < 0.05), whereas it decreased by 50-80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations.
In conclusion, 1) acute AT1 blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are >85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system.
sodium excretion; blood pressure; glomerular filtration rate; NG-nitro-L-arginine methyl ester; candesartan
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE CONTROL OF RENAL SODIUM excretion is multifactorial, involving physical, neural, and humoral mechanisms. However, the relative contributions of the individual components are still unclear, e.g., evaluation of the importance of the renin-angiotensin system vs. the role of nitric oxide (NO) in renal sodium homeostasis is particularly complex. The natriuretic effect of volume expansion is linked to a decrease in plasma levels of ANG II (e.g., 3, 32), and an intact NO synthesis is also a prerequisite for volume expansion natriuresis (21, 26). However, the relative importance and possible interaction between the two systems are poorly elucidated in conscious animals. We recently demonstrated (2) that a slow, moderate volume expansion in the absence of ANG II (due to converting enzyme inhibition) elicited a marked exaggeration of the natriuresis seen in control dogs, although blood pressure did not increase above preinhibition control. We also observed that most of this natriuretic response was preserved when increases in blood pressure during volume expansion were totally prevented by concomitant administration of nitroprusside. Thus the exaggeration of the volume expansion natriuresis was not related to any blood pressure change. However, it remains a possibility that NO released from this drug was, at least partly, responsible for the observed natriuresis. NO is a vasorelaxant molecule formed from the conversion of L-arginine by NO synthase (NOS) in endothelial cells in response to a variety of stimuli (13, 14, 25). It can be competitively blocked by structural analogs, e.g., NG-nitro-L-arginine methyl ester (L-NAME). In the present study, we aimed to prevent the effects of ANG II by specific AT1-receptor blockade and in this condition investigate the role of NO in volume expansion natriuresis by use of NOS inhibition. In conscious dogs, the concomitant hemodynamic, renal, and hormonal responses to volume expansion during acute AT1-receptor blockade and/or NOS inhibition were observed, and in separate experiments, the effects of AT1-receptor blockade per se were recorded.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Experiments were performed in six conscious female Beagle dogs weighing 10.0-15.0 kg. The dogs were part of a pool of animals used in this and other projects; they were kept on a fixed diet (Special Diets Services, Witham, United Kingdom) and received one meal a day around 1400. Mean daily sodium intake was 2.2 ± 0.1 mmol/kg body wt. The dogs had free access to tap water. Before the study, all animals underwent two surgical interventions. Displacement of both common carotid arteries into skin loops and a chronic episiotomy were performed to make catheterization of the arterial system and the bladder more easy, and a bilateral oophorosalphingohysterectomy was performed to avoid cyclic alterations in hormones (see Ref. 3 for details). Complications after surgery did not occur, and the dogs were trained for several months before experiments. The experimental procedures were approved by the Danish Animal Experiments Inspectorate.
Experimental protocol.
The same six dogs were used for all experiments. In each dog,
experiments were performed at intervals of at least 1 wk. At midnight
before the experiment, an electric valve controlled by a timer
interrupted the water supply. Baseline conditions were thus
characterized by 9 h of water deprivation. The dog was transferred to the laboratory at 0800. A sterile catheter (Intracath, Becton Dickinson, Sandy, UT) was introduced into the right atrial area via the
external jugular vein and used for infusions. Another catheter
(Insyte-W, Becton Dickinson) was placed in a common carotid artery
allowing continuous measurements of blood pressure interrupted by
periodic sampling of arterial blood. A modified silicone Foley catheter
(Norta, Beiersdorf, Hamburg, Germany) was used for catheterization of
the bladder. An intravenous bolus of creatinine (8.2 ml 
14 mg/kg) was given 1 h before the start of the experiment followed by a continuous infusion (7.2 ml/h 0.21 mg · kg1 · min1) throughout
the experiment. In the case of AT1-receptor blockade, a
bolus injection of candesartan (1 mg/kg, courtesy of Dr. P. Morsing,
AstraZeneca, Mölndal, SE) was administered at t = 30 min (C series) or 1 h before the start of the experiment (Fig. 1): 15 mg candesartan was dissolved in a
mixture of 4.5 ml glucose/urea solution and 0.5 ml
Na2CO3 solution (106 g/l), and 5.0 ml
glucose/urea solution was added. In the case of NOS inhibition, a
continuous infusion of L-NAME (30 µg · kg1 · min1; Sigma
Chemical, St. Louis, MO) was initiated 1 h before the start of the
experiment (Fig. 1): 100 mg L-NAME was dissolved in 20 ml
of sterile water and infused at a rate of 0.006 ml · kg1 · min1. In the
case of volume expansion, infusion of saline was initiated after one
30-min control period and continued for 90 min (t = 30-120 min) at a dose of 60 µmol · kg1 · min1,
corresponding to a rate of 0.39 ml · kg1 · min1 (Fig. 1).
One 30-min recovery period completed the experiment (t = 120-150 min). Urine was sampled every 30 min.
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5 min for determination of plasma creatinine, and afterwards, samples were obtained 25 min into each sampling period. Samples of 1 ml drawn
at t = 55 and 85 min were used for creatinine
determination, whereas electrolyte, osmolality, protein, hormone, and
creatinine concentrations were measured from 16-ml samples obtained at
t = 25, 115, and 145 min.
Arterial blood pressure was measured continuously by a pressure
transducer (Statham P50, Gould) connected to a clinical monitor (Dialogue 2000, Danica Elektronik, Rødovre, Denmark). This provided mean arterial blood pressure from the pressure signal on the basis of a
300-Hz analog-to-digital sampling frequency over a 7-s time window.
Heart rate (HR) was obtained from the electrocardiogram. The monitor
data were sampled every 10 s by computer and subsequently averaged
over 30-min periods.
The responses to AT1-receptor blockade and to volume
expansion in the presence of AT1 blockade and/or NOS
inhibition were investigated in separate experimental series:
1) control series (control); no intervention, 2)
candesartan series (C); bolus injection of candesartan at
t = 30 min, 3) candesartan + isotonic
series (CI); bolus injection of candesartan at t = 60
min and volume expansion at t = 30-120 min,
4) candesartan + isotonic + L-NAME series (CIL); bolus injection of candesartan at t = 60 min, volume expansion at t = 30-120 min, and
continuous infusion of L-NAME at t = 60-150 min, and 5) isotonic + L-NAME
series (IL); volume expansion at t = 30-120 min
and continuous infusion of L-NAME at t = 60-150 min.
Analyses. The concentrations of sodium and potassium ions in plasma and urine were measured by flame photometry (IL243 flame photometer, Instrumentation Laboratory, Lexington, MA). Plasma and urine osmolality were determined by freezing-point depression (Advanced Instruments, Needham Heights, MA). Plasma protein concentration was measured by a refractometer (model T2-NE, Atago, Tokyo, Japan). Concentrations of creatinine in urine and plasma were measured by Jaffé's reaction modified from Bonsnes and Taussky (5).
Hormones. The analyses of hormone levels in plasma were performed by radioimmunoassay after extraction as described previously (11). Results are not corrected for incomplete recovery.
ANG II. To determine ANG II immunoreactivity in plasma, a specific antibody (Ab-5-030682) produced by P. Christensen was used at a final dilution of 1:1,100,000 as recently described (3). The detection limit was <1.4 pg/ml, and the mean recovery of unlabeled ANG II added to plasma before extraction was 88%. Intra- and interassay coefficients of variation were 5 and 12%, respectively.
Aldosterone. Plasma aldosterone was measured using a commercial kit (COAT-A-COUNT, Diagnostic Products, Los Angeles, CA). Detection limit was 13.0 pg/ml, and intra-assay coefficient of variation was <4%.
Atrial natriuretic peptide. A specific antibody (AB95069/5) produced in this laboratory was used in a final dilution of 1:27,000 according to the procedure of Schütten et al. (31). The detection limit was 1.5 pg/ml, and the mean recovery of unlabeled atrial natriuretic peptide (ANP) added to plasma before extraction was 74%. The intra- and interassay coefficients of variation were 6 and 8%, respectively.
Vasopressin. Plasma arginine vasopressin (AVP) was measured using an antibody (AB3096) produced in this laboratory. The assay was performed according to Emmeluth et al. (12), and the antibody was used at a final dilution of 1:800,000. The detection limit was <0.2 pg/ml, and the mean recovery of unlabeled AVP added to plasma before extraction was 66%. Intra- and interassay coefficients of variation were <8%.
Statistics. Data are presented as means ± SE. The results were evaluated by one-way ANOVA for repeated measurements within groups and between groups at the control level and at the time of maximal effect. If the ANOVA indicated significance (P < 0.05), all differences between means were investigated systematically by Newman-Keuls test. In the case of inhomogeneity of variances, data were logarithmically transformed before analysis. P values smaller than 0.05 were considered to indicate significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Systemic hemodynamics.
AT1-receptor blockade reduced mean arterial blood pressure
for the duration of the experiment (C series; Fig.
2), and blood pressure fell immediately
from 106 ± 4 mmHg and a nadir of 96 ± 5 mmHg occurred 150 min after administration. Subsequent volume expansion (CI series; Fig.
3) was associated with a significant increase of 11 ± 2 mmHg in blood pressure (from 97 ± 5 mmHg). Simultaneous AT1-receptor blockade and NOS
inhibition (CIL series; Fig. 3) did not seem to affect blood pressure
before volume expansion, but subsequent volume expansion was associated
with a marked increase of 21 ± 4 mmHg (from 107 ± 3 mmHg).
NOS inhibition per se (IL series; Fig. 3) was associated with an
increase in blood pressure to 116 ± 3 mmHg, which was enhanced by
9 ± 3 mmHg by additional volume expansion. In the control
experiments, there were no changes in blood pressure.
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Renal variables.
Administration of candesartan per se led to an increased rate of
urinary sodium excretion (C and CI series; Figs. 2 and
4) compared with control experiments
where sodium excretion was low and constant between 10 ± 3 and
14 ± 3 µmol/min. AT1-receptor blockade (C series;
Fig. 2) increased sodium excretion from 12 ± 1 to 34 ± 6 µmol/min, and additional volume expansion (CI series; Fig. 4) caused
a marked increase in sodium excretion from a baseline of 26 ± 11 µmol/min, reaching a maximum of 274 ± 55 µmol/min in the
third infusion period. At the end of the experiment, sodium excretion
was still substantially elevated (210 ± 32 µmol/min). Administration of L-NAME had the reverse effect on renal
sodium handling (IL series; Fig. 4). The control value was reduced to 2 ± 1 µmol/min, and the response to subsequent volume expansion was likewise reduced to a maximum of only 23 ± 7 µmol/min.
During concomitant infusion of candesartan and L-NAME (CIL
series; Fig. 4), the control value was not different from control
experiments (10 ± 3 vs. 14 ± 3 µmol/min). It appears that
the opposite effects of the two drugs neutralized each other, leaving
no net response. The response to subsequent volume expansion was
reduced to a maximum of 45 ± 11 µmol/min.
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1 · min1) after
termination of the C experiments, and in no case did changes in blood
pressure occur. Normal pressor response to this dose was some 30 mmHg.
Hormones.
Plasma concentrations of ANG II were substantially increased in
response to administration of candesartan compatible with AT1-receptor blockade (Table
3). Values varied between 69 ± 17 and 163 ± 54 pg/ml compared with control values of ~10
pg/ml. Volume expansion was invariably associated with a significant decrease in plasma ANG II (>50%). Aldosterone is normally released in
response to AT1-receptor stimulation, and accordingly,
plasma concentrations of aldosterone decreased below detection limit in
all series involving administration of candesartan. In the series with
L-NAME and volume expansion (IL), significant decreases were observed. Plasma concentrations of AVP were unaffected by the
involved procedures. Plasma concentrations of ANP were observed to
decrease in response to AT1-receptor blockade (C). As
expected, subsequent volume expansion led to a significant but small
increase in plasma ANP (CI). However, infusion of L-NAME
seemed to abolish the ANP response to volume expansion (CIL, IL).
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Plasma electrolytes, osmolality, and protein concentration. Plasma sodium concentrations varied between 142.0 ± 0.4 and 144.0 ± 0.5 mmol/l and showed no significant alterations (Table 1). Plasma potassium concentrations remained unchanged in all experiments except for an increase of 0.3 mmol/l in the recovery period during CIL and IL where a decrease of 0.1 mmol/l during volume expansion reached significance. Plasma osmolality varied slightly (between 300.7 ± 1.1 and 306.2 ± 0.6 mosmol/kgH2O) but unsystematically and <1% within any one series. Plasma protein decreased significantly in all series except C.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major findings of the present experiments were 1) that AT1-receptor blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) that these responses are >85% inhibitable by NOS inhibition, and 3) that NOS inhibition alone virtually abolishes the volume expansion natriuresis.
Administration of candesartan at a dose of 1 mg/kg seemed to establish an effective AT1-receptor blockade and caused hypotension, natriuresis, and an increase in glomerular filtration rate (GFR) (Fig. 2). As mentioned above, the acute effects of this drug were compared with another AT1-receptor antagonist, and very similar actions were observed, and infusion of ANG II in a rather large dose after the end of the experiment did not cause any increase in blood pressure. The effects of ANG II-receptor antagonists on renal function observed in the present study are in accordance with other investigations (e.g., Ref. 17), although it must be noted that the subject has been submitted to numerous investigations and the results have been quite variable (7, 8, 18, 24, 33, 35, 36). In accordance with the major part of the literature, however, intravenous administration of AT1-receptor blockers is accompanied by diuresis and natriuresis, and in addition, mostly by increases in GFR and renal blood flow.
Volume expansion in the presence of AT1-receptor blockade was observed to elicit a profuse natriuresis. Compared with control experiments during which dogs under very similar circumstances underwent an identical experimental protocol except for the AT1-receptor blockade (3), the present profuse natriuresis represents a doubling of the natriuretic effect, which, in the previous study, was considered very substantial because it represented approximately a 100-fold increase over control. This lower natriuretic response to volume expansion without blockade is most likely due to the antinatriuretic effect of the remaining activity of the low concentration of ANG II in plasma (3.7 pg/ml). Experiments with volume expansion followed by AT1-receptor blockade would test this hypothesis, but such experiments have not been performed.
NO is synthesized in the kidney and is a potent renal vasodilator and natriuretic substance (13, 14, 25, 30, 34, 37). The importance of this mechanism under normal physiological conditions is emphasized by our finding that NOS inhibition reduced baseline sodium excretion by some 80%. Several studies provided evidence that NO synthesis is increased in response to acute and chronic elevations in extracellular fluid volume (9, 16, 22, 28). In addition, blockade of NO synthesis has been reported to attenuate the natriuretic response to an isotonic saline load (21, 26, 27). However, Krier and Romero (19) showed that NOS inhibition alone impaired volume-induced natriuresis in a manner that required further increases in blood pressure to restore the natriuresis. Our finding that NOS inhibition leads to severe suppression of the natriuretic response to volume expansion supports these results and leaves open the possibility that modest changes in the synthesis of NO either participates in the regulation of renal sodium or is a permissive factor allowing another regulatory system to exert its full effect. The present experiments do not allow a distinction between the two possibilities. Another possible explanation for the NOS inhibition-induced suppression of the natriuretic response to volume expansion could be changes in circulating levels of ANG II. NOS inhibition per se doubled plasma ANG II, and additional volume expansion was associated with a decrease not different from control level. However, the finding that NOS inhibition is associated with increments in plasma ANG II is in direct contrast to the major part of the literature (15).
From the previous paragraphs, it appears that AT1-receptor blockade and NOS inhibition have opposite effects with regard to renal sodium handling. To further elucidate the relative importance of and possible interaction between the two systems, both substances were administered simultaneously, and volume expansion was performed in the presence of both AT1 receptor and NOS inhibition. The outcome with regard to renal sodium excretion was first that simultaneous AT1-receptor blockade and NOS inhibition did not alter baseline values compared with control experiments in untreated dogs, and second, that additional volume expansion led to a marked attenuation (>85%) of the pronounced natriuresis observed with AT1-receptor blockade alone. These findings indicate that the effects of the two drugs also on a quantitative basis counteracted each other, leaving almost no room for a net response.
The effects on renal sodium excretion were closely related to changes in GFR and might be influenced by this variable. AT1-receptor blockade per se increased GFR by 17%; additional volume expansion by an additional 30%. NOS inhibition alone decreased GFR by 21%, and additional volume expansion tended to increase GFR, but the change did not reach statistical significance. Volume expansion during combined drug administration increased GFR by 13%. From the present data, it is not possible to determine the intrarenal mechanisms by which GFR was altered. The fact that AT1-receptor blockade increases GFR, as discussed above, has been established through numerous studies. However, the observation that NOS inhibition alone decreased GFR is not compatible with the findings of Salazar's group (1, 21, 29), who showed repeatedly that blockade of NO did not induce changes in renal hemodynamics including GFR. Other investigators, however, reported findings similar to those of the present study (20, 26). The diversity of observations on this matter is not immediately intelligible, but it may reflect different experimental protocols and/or species differences. In the present study, a substantial dose of L-NAME was used to ensure marked inhibition of NO synthesis. However, this may affect hemodynamic conditions to an unphysiological extent.
Changes in oncotic pressure might influence renal sodium handling under the present conditions. From a study in conscious dogs, Cowley and Skelton (10) concluded that the diuresis and natriuresis following isotonic volume expansion are a result predominantly of plasma protein dilution. Bie and Sandgaard (3) observed a decrease in oncotic pressure of ~19% in response to an identical volume expansion. In the present study, plasma protein was observed to decrease in all series involving volume expansion. However, numerically, the lowest level was found in the series with blunted diuretic and natriuretic responses compared with the series with profuse diuresis and natriuresis. Therefore, if oncotic pressure changes did contribute to the present differences in sodium excretion between series in response to volume expansion, the effect was probably minor.
The difference between the natriuretic responses to volume expansion might a priori be attributed to the natriuretic effect of ANP. However, in the absence of other changes, plasma ANP must be elevated rather substantially to induce an immediate natriuresis (4, 6). The present changes appear very small in this context, and the plasma levels of this hormone corresponding to peak sodium excretion in the three series involving volume expansion were identical. Therefore, the different natriuretic responses measured under the present conditions cannot, to any significant extent, be explained by changes in plasma ANP.
Perspectives
The present study provides further evidence that NO plays an important role in the maintenance of renal sodium homeostasis. From previous and the present data, we speculate that under normal physiological conditions, even modest increases in renal sodium excretion are preceded by and, to a large extent, regulated by a decrease in the action of the renin system and that an intact NO system is required for this system to be fully operative. With the present design, it is not possible to account for the pathway of signaling linking volume expansion to natriuresis under conditions when both the renin and NO system have been knocked out, nor is it possible to evaluate the intrarenal routes of action of either candesartan or L-NAME. NO may exert a permissive effect on renal sodium handling, i.e., a certain activity is a necessary prerequisite for other systems to be fully operative, or it may work as a primary controller playing in concert with other control systems. One possible scenario would include a permissive effect of NO under normal physiological circumstances, whereas a role as a primary controller of sodium homeostasis may be restricted to situations where ANG II and blood pressure, the two major controllers, are disabled. Further investigation of the interaction between NO generation and other natriuretic stimuli may provide novel data with regard to the role of NO in the physiological regulation of renal sodium excretion.| |
ACKNOWLEDGEMENTS |
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The expert technical assistance of S. K. Hansen in the dog laboratory and of I. H. Pedersen, T. Eidsvold, B. Sørensen, and B. A. Kristensen with the analyses is gratefully appreciated. Aprotinine was kindly provided by Novo Nordisk AS.
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FOOTNOTES |
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The work was supported by grants from Konsul Ehrenfried Owesén og Hustrus Foundation, Gerda og Aage Haensch's Foundation, "Fonden til Lægevidenskabens Fremme," and the Danish Medical Research Council.
Address for reprint requests and other correspondence: P. Bie, Dept. of Physiology and Pharmacology, Univ. of Southern Denmark, 21 Winsløwparken, DK-5000 Odense C, Denmark (E-mail: pbie{at}health.sdu.dk).
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.
10.1152/ajpregu.00665.2000
Received 17 October 2000; accepted in final form 11 December 2001.
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TOP
ABSTRACT
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METHODS
RESULTS
DISCUSSION
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: candesartan 1 mg/kg at t = 30 min.
Values are means ± SE. * Significantly different
(P < 0.05) from control value (0-30 min).
: CI series; 
: CIL series;
: IL series. Candesartan 1 mg/kg at t = 
Significantly different
(P < 0.05) from control series.
