Spontaneous renal blood flow autoregulation curves in conscious sinoaortic baroreceptor-denervated rats

Silene L. S. Pires, Claude Julien, Bruno Chapuis, Jean Sassard, and Christian Barrès

Centre National de la Recherche Scientifique Unité Mixte de Recherche 5014, Institut Fédératif de Recherche Cardio-vasculaire 39, Faculté de Pharmacie, Université Claude Bernard Lyon 1, Lyon 69373, France


    ABSTRACT
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

These experiments examined whether the conscious sinoaortic baroreceptor-denervated (SAD) rat, owing to its high spontaneous arterial pressure (AP) variability, might represent a model for renal blood flow (RBF) autoregulation studies. In eight SAD and six baroreceptor-intact rats, AP and RBF were recorded (1-h periods) before and after furosemide (10 mg/kg followed by 10 mg · kg-1 · h-1 iv) administration. In control conditions, AP variability was markedly enhanced in SAD rats (coefficient of variation: 16.0 ± 1.2 vs. 5.4 ± 0.5% in intact rats), whereas RBF variability was only slightly increased (8.7 ± 0.6 vs. 6.1 ± 0.5% in intact rats), suggesting buffering by autoregulatory mechanisms. In SAD rats, but not in intact rats, the AP-RBF relationships could be modeled with a four-parameter sigmoid Weibull equation (r2 = 0.24 ± 0.07, 3,600 data pairs/rat), allowing for estimation of an autoregulatory plateau (10.1 ± 0.7 ml/min) and a lower limit of RBF autoregulation (PLL = 93 ± 6 mmHg, defined as AP at RBF 5% below the plateau). After furosemide treatment, autoregulation curves (r2 = 0.49 ± 0.07) in SAD rats were shifted downward (plateau = 8.6 ± 0.8 ml/min) and rightward (PLL = 102 ± 5 mmHg). In five of six intact rats, PLL became measurable (104 ± 1 mmHg), albeit with limited accuracy (r2 = 0.09 ± 0.03). In conclusion, the conscious SAD rat offers the possibility of describing RBF autoregulation curves under dynamic, unforced conditions. The tubuloglomerular feedback and myogenic mechanisms cooperate in setting PLL and thus in stabilizing RBF during spontaneous depressor episodes.

arterial pressure variability; furosemide; modeling


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

AUTOREGULATION OF TOTAL RENAL blood flow (RBF) is usually explored by measuring RBF responses to externally induced stepwise reductions of arterial pressure (AP) in both anesthetized (6, 8, 11, 13, 17, 21, 22) and conscious (2, 4, 16, 18, 24-26) animals. Steady-state levels of RBF are plotted as a function of AP, which allows the drawing of autoregulation curves from which the plateau and lower pressure limit of RBF autoregulation (PLL) are estimated. It is not known whether such information can be gained under spontaneous unforced conditions, i.e., using RBF responses to naturally occurring AP fluctuations.

The conscious sinoaortic baroreceptor-denervated (SAD) rat is a well-recognized model of exaggerated AP variability, which is characterized by the spontaneous occurrence of pressor and depressor episodes of occasionally large amplitude (3, 28). Recently, we have investigated in conscious SAD rats the relationships between AP variability and RBF variability (20). Although AP variability was markedly increased, RBF variability was only slightly increased, suggesting a powerful participation of autoregulatory mechanisms in stabilizing RBF. However, spectral analysis of AP and RBF time series revealed that in this model, despite potent autoregulatory responses, large low-frequency (0.001-0.1 Hz) AP fluctuations were likely to induce RBF fluctuations. Time-domain analysis of these data indicated that acute hypertensive episodes were not associated with parallel increases in RBF. On the contrary, three-dimensional frequency distributions of AP-RBF data pairs (Fig. 1B in Ref. 20) indicated that the lowest RBF values were frequently associated with the lowest AP values. These observations suggested that some RBF decreases in SAD rats may be secondary to spontaneous AP decreases below PLL.

In the present study, we hypothesized that the conscious SAD rat could represent an alternative model for describing RBF autoregulation curves. Because it has been shown that changes in renal sympathetic nerve activity can alter RBF (1, 10) and modulate PLL (18), the kidney used for RBF recording was denervated.

With the use of stepwise reductions of AP, it has been shown that blockade of tubuloglomerular feedback (TGF) activity results in a significant impairment of RBF autoregulation (8, 16, 25, 26), suggesting that the autoregulatory efficiency is dependent on the TGF mechanism. However, using spectral analysis of AP and RBF in conscious dogs, it has also been reported that the TGF mechanism was not required for RBF autoregulation in response to spontaneously occurring AP changes (16). Therefore, to evaluate the participation of the TGF mechanism in RBF responses to spontaneous variations of AP in the conscious SAD rat, hemodynamic recordings were performed before and after administration of furosemide, a potent inhibitor of TGF activity (27).


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animal preparation. All experiments were conducted in accordance with the guidelines of the French Ministry of Agriculture for animal experimentation. Fourteen male Sprague-Dawley rats, weighing 250-300 g (Iffa-Credo, L'Arbresle, France), were used and prepared as previously described (20). Briefly, 14 days before the beginning of the study a bilateral sinoaortic baroreceptor denervation was performed in eight rats. One week later, SAD rats and six baroreceptor-intact rats were submitted to left renal denervation and instrumented with an ultrasonic transit-time flow probe (1RB, Transonic Systems, Ithaca, NY) around the left renal artery for RBF measurement. Five days later, i.e., 2 days before the beginning of the study, femoral arterial and venous catheters were inserted for AP measurement and drug administration, respectively. Both catheters and the probe cable were exteriorized between the scapulae and protected in a small plastic cap sewn to the skin. Antibiotic (neomycin sulfate) was applied topically. After each intervention, rats received a single injection of penicillin G (40,000 IU ip).

Measurements. AP was measured by connecting the arterial catheter to a precalibrated pressure transducer (TNF-R, Ohmeda, Bilthoven, The Netherlands) through a two-way stopcock, which allowed the continuous infusion of a 5% glucose solution (0.5 ml/h). The pressure transducer was coupled to an amplifier (model 13-4615-52, Gould, Cleveland, OH)- chart recorder (model 8802, Gould). Absolute RBF was measured with a flowmeter (T106, Transonic Systems) without filtering. After analog-digital conversion (AT-MIO-16E converter board, National Instruments, Austin, TX), AP and RBF signals were simultaneously and continuously recorded on a computer (500-Hz sampling rate) using LabVIEW 5.0 software (National Instruments).

Experimental protocol. All recordings were performed while the rats were conscious and unrestrained. AP and RBF were recorded continuously during two consecutive periods of 1-h duration each. The first 1-h recording period occurred without any pharmacological intervention and was initiated after stabilization of cardiovascular variables. The second 1-h recording period started 10 min after an intravenous bolus injection of furosemide (10 mg/kg, Lasilix, Hoechst Houdé), followed by a continuous intravenous infusion of 10 mg · kg-1 · h-1 maintained until completion of the study. The infusion flow rate was 1 ml · kg-1 · h-1. Rats had free access to water throughout the study. At the end of the experiment, rats received an intravenous overdose of pentobarbital sodium, and both kidneys were removed, weighed, and frozen for subsequent determination of norepinephrine concentration (9).

Data analysis. The individual 500-Hz data files were first replayed and carefully examined to eliminate occasionally occurring artifacts. The 500-Hz data files were resampled at 1 Hz by averaging over consecutive 1-s periods for subsequent analysis. Therefore, each 1-h experimental period consisted of 3,600 AP-RBF data pairs.

From each 1-h period, the 3,600 AP-RBF data pairs were sorted according to an ascending-order AP, and AP and corresponding RBF values were averaged within 2.5-mmHg intervals. After the AP intervals that were common to all SAD or intact rats were considered, average RBF values were plotted as a function of AP in each group of rats.

Finally, the equation of a sigmoidal model was fitted to the different sets of experimental data (3,600 individual data pairs, individual data organized in AP intervals, and group-average data organized in AP intervals), using an iterative least-squares procedure (SigmaPlot 5.0, SPSS, Chicago, IL).

In each rat and for each period, the overall spontaneous variability of AP and RBF was estimated by calculating the coefficient of variation of 1-Hz data.

Statistics. All data are presented as means ± SE. Comparisons between intact and SAD rats were performed with the use of the nonparametric Mann-Whitney U-test. Within each group of rats, comparisons between periods were performed by using the Wilcoxon signed-rank test.


    RESULTS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Body weights were similar in intact (331 ± 13 g) and SAD (322 ± 9 g) rats. Norepinephrine concentrations in the left kidney (12.2 ± 2.7 and 15.5 ± 7.5 ng/g kidney wt in intact and SAD rats, respectively) were reduced by >90% compared with the norepinephrine concentrations measured in the right kidney (141 ± 12 and 240 ± 25 ng/g kidney wt in intact and SAD rats, respectively).

As indicated in Table 1, in control conditions chronic sinoaortic denervation did not modify the 1-h mean levels of AP and RBF but induced a threefold increase in AP variability and a 40% increase in RBF variability. Furosemide administration increased AP and decreased RBF in intact rats, whereas it decreased both AP and RBF in SAD rats. In addition, after furosemide, the RBF variability was increased in both groups of rats without a significant change in AP variability.

                              
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Table 1.   One-hour average values of mean level and variability for AP and RBF in conscious intact and SAD rats before and after furosemide administration

Group-average RBF autoregulation curves. Figure 1 summarizes the spontaneous RBF-AP relationships observed in six intact (A) and eight SAD (B) rats after data reduction in 2.5-mmHg AP intervals. In intact rats with low AP variability, a zone of nonefficient autoregulation (RBF decreases associated with AP decreases) was not clearly apparent in control conditions. By contrast, in SAD rats with high AP variability, a plateau and a zone of nonefficient autoregulation could be clearly identified in control conditions. Such a profile with a plateau and a zone of nonefficient autoregulation was also observed in both intact and SAD rats after furosemide.


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Fig. 1.   Spontaneous relationships between arterial pressure (AP) and renal blood flow (RBF) recorded during 1-h periods in 6 conscious baroreceptor-intact rats (A) and 8 conscious sinoaortic baroreceptor-denervated (SAD) rats (B) before () and after (open circle ) furosemide administration. In each rat, AP-RBF data pairs (n = 3,600) were first averaged within 2.5-mmHg intervals. Group-average data (±SE) were then calculated for AP intervals that were common to all animals (except above 115 mmHg in SAD rats after furosemide). Solid lines are plots of the 4-parameter Weibull equation that was fitted to experimental data. Note that in intact rats in control conditions, the model could not be fitted. The horizontal and vertical dotted lines show estimates of plateau and lower pressure limit of RBF autoregulation (PLL) that were derived from the model (see RESULTS).

Because this profile matched a portion of a sigmoidal curve, the equations of various sigmoidal models were tested for fitting to experimental data. The four-parameter Weibull equation was found to satisfactorily fit to experimental data (r2 = 0.984, n = 28 AP intervals, P < 0.0001 in SAD rats in control conditions; r2 = 0.997, n = 27 AP intervals, P < 0.0001 in SAD rats after furosemide; r2 = 0.935, n = 17 AP intervals, P < 0.0001 in intact rats after furosemide). The equation of the model is
RBF<IT>=a</IT><FENCE>1<IT>−e</IT><SUP>−</SUP><FENCE><FR><NU>AP<IT>−x</IT><SUB>0</SUB><IT>+b</IT>(ln 2)<SUP>1<IT>/c</IT></SUP></NU><DE><IT>b</IT></DE></FR></FENCE><SUP><IT>c</IT></SUP></FENCE>
where a is the upper plateau of the sigmoid, x0 is the AP at the RBF value corresponding to half the plateau, and b and c are scale and shape parameters of the Weibull distribution, respectively. From the fitted curves (Fig. 1), PLL was computed as the AP corresponding to the RBF value 5% lower than the estimated plateau. In SAD rats, plateau and PLL were found at 9.9 ml/min and 89 mmHg and at 8.5 ml/min and 101 mmHg in control conditions and after furosemide, respectively. In intact rats after furosemide, the plateau and PLL were 9.2 ml/min and 105 mmHg.

Analysis of individual autoregulation curves. In a second step, the model was fitted to individual data organized in AP intervals of 2.5 mmHg (Figs. 2C and 3C). If the estimated plateau was not reached by the experimental data or if no data point was present below the estimated PLL, the fitting was not considered. According to these criteria, in control conditions plateau and PLL could not be determined in intact rats and were estimated in five of eight SAD rats. After furosemide, plateau and PLL were estimated in three of six intact rats and in six of eight SAD rats.


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Fig. 2.   Original 1-Hz time series of AP and RBF (A) and corresponding AP-RBF relationships obtained before (B) and after (C) data reduction in 2.5-mmHg AP intervals in 1 conscious baroreceptor-intact rat before (left) and after (right) furosemide administration. Only AP intervals containing at least 10 data pairs were considered. Solid lines in the scatterplots show the fitted model, and horizontal and vertical dotted lines indicate estimates of the plateau and PLL, respectively. In one case (AP intervals, control), the model estimate of the plateau was 23.1 ml/min, which largely exceeded the range of actual RBF variations. Consequently, the plateau and PLL are not reported. Note that this intact rat is the only one in which the model could be fitted to the 3,600 data pairs in control conditions.



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Fig. 3.   Original 1-Hz time series of AP and RBF (A) and corresponding AP-RBF relationships obtained before (B) and after (C) data reduction in 2.5-mmHg AP intervals in 1 conscious SAD rat before (left) and after (right) furosemide administration. Only AP intervals containing at least 10 data pairs were considered. Solid lines in the scatterplots show the fitted model, and horizontal and vertical dotted lines indicate estimates of the plateau and PLL, respectively. Note the exaggerated AP variability and the occurrence of simultaneous AP and RBF decreases, especially after furosemide.

When the model was applied to the individual sets of 3,600 data pairs obtained initially in each intact and SAD rat (Figs. 2B and 3B), it was found to satisfactorily fit to data in the eight SAD rats in both experimental conditions (Table 2). In intact rats, the model was able to fit to experimental data in one of six rats in control conditions and in five of six rats after furosemide (Table 2). In SAD rats after furosemide, the plateau was significantly decreased and PLL was increased (Table 2). In addition, the percentage of data pairs below PLL was markedly increased after furosemide (Table 2). PLL values were comparable in both intact and SAD rats after furosemide. Figure 4 summarizes the individual fitted curves for SAD rats and shows the average model for each condition. The PLL values calculated from the average models were similar to the mean values presented in Table 2.

                              
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Table 2.   Characteristics of RBF autoregulation curves obtained from nonlinear modeling of individual sets of 3,600 data pairs



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Fig. 4.   Individual fitted curves (thin lines) obtained by applying the 4-parameter Weibull model to 3,600 AP-RBF data pairs in SAD rats before (A) and after (B) furosemide administration. Individual estimates of parameters were averaged to plot the average model (thick lines).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The major finding of this study is that the conscious SAD rat, having high spontaneous AP variability, may represent a convenient model for studying the characteristics of RBF autoregulation. The frequent occurrence of large pressor and depressor episodes permitted the study of RBF responses over a wide range of AP fluctuations. After AP-RBF relationships were modeled with a sigmoid equation, an autoregulatory plateau and PLL were identifiable. Under control conditions, PLL was found to be ~90 mmHg. After inhibition of the TGF mechanism with furosemide, PLL was shifted to ~100 mmHg.

In baroreceptor-intact rats, AP fluctuations occurred mainly in the RBF autoregulatory range, which precluded the determination of pressure limits of RBF autoregulation. After SAD, large spontaneous dips in AP were frequently associated with decreases in RBF, suggesting that autoregulatory mechanisms were unable to maintain RBF during these depressor episodes. Classically, in studies using artificially induced AP reductions, PLL is determined from autoregulatory curves exhibiting a plateau and a subautoregulatory zone (2, 4, 17, 18, 21, 22, 24). From SAD rat raw data, even after being resampled at 1 Hz, the drawing of autoregulation curves was not obvious, because of the large spontaneous variability of RBF. Averaging RBF data over 1-s periods eliminated most of the respiratory fluctuations and compliance effects, which predominate at frequencies above 1 Hz (20). At lower frequencies, sources of RBF variability include a prominent oscillation of ~0.25-Hz frequency related either to vasomotion or to the resonance of myogenic responses (7) and a slower oscillation, centered around 0.05 Hz, that probably derives from instability in the TGF loop (12). It is likely that the averaging procedure within 2.5-mmHg intervals effectively limited the influence of such RBF fluctuations without affecting the global trends of the AP-RBF relationships, as similar autoregulatory curves were obtained before and after data reduction in AP intervals (Fig. 3, B and C). The 2.5-mmHg range for AP intervals was chosen to favor the presence of several data pairs in each AP interval, especially in the lowest and highest AP ranges. In addition, this procedure of data reduction offered the possibility of easily obtaining mean RBF autoregulatory curves in a given group of rats (Fig. 1). From RBF autoregulatory curves, several methods have been proposed for the determination of PLL. It is frequently calculated as the intersection of the two straight lines corresponding to the autoregulatory plateau and to the subautoregulatory zone after the data points were fitted either by eye (21) or by progressive linear regression (17, 18). Recently, a new method of determination has been proposed (22). After the AP-RBF data pairs are subjected to nonlinear regression analysis using a sigmoid equation, PLL is defined as the AP where the third derivative of the fitted curve is null, which mathematically corresponds to the shoulder in a sigmoidal curve. When the averaged AP-RBF data pairs corresponding to the SAD group in control conditions were submitted to nonlinear regression analysis using the three-parameter sigmoid equation, an excellent coefficient of determination was obtained (0.971 with 28 AP intervals). When the same data were submitted to nonlinear regression analysis using the four-parameter Weibull equation, although the coefficient of determination was only slightly improved, the fitted curve was found to more accurately describe the region at the break-off point of the autoregulatory curve (see Fig. 1). Because similar observations were made from fittings of RBF autoregulation curves obtained in SAD or intact rats after furosemide, the Weibull equation was preferred to the three-parameter sigmoid equation. After modeling, PLL was calculated as the AP where the fitted RBF was equal to 95% of the plateau. This value calculated from the autoregulatory curve obtained in the group of SAD rats under control conditions (89 mmHg) was intermediate to PLL calculated by the third derivative method (86 mmHg) or estimated by eye (92 mmHg). Similar observations were made in both SAD and intact rats after furosemide treatment. Because the four-parameter Weibull equation was not able to fit all individual experimental data obtained in SAD rats under control conditions, we applied the model to the 1-Hz data sets. A plateau and PLL were measurable in all SAD rats, whatever the experimental condition, and in five of six intact rats after furosemide.

The estimated PLL value in conscious SAD rats under control conditions (93 ± 6 mmHg) agrees well with previous observations made in conscious intact normotensive rats using artificially induced stepwise reductions of AP [~90 mmHg in Long-Evans rats (4), 88 ± 2 mmHg in Wistar rats (24), and 98 ± 3 mmHg in Sprague-Dawley rats (2)]. Such a similarity strongly suggests that classic methods, based on the observation of steady-state effects, and the present one, based on the observation of dynamic responses, explore the same phenomena. This would imply that the largest depressor episodes in SAD rats induced a maximal activation (saturation) of autoregulatory mechanisms. We have previously shown that spontaneous AP fluctuations in SAD rats are able to induce powerful renal autoregulatory responses. Furthermore, as could be assessed from transfer-function analysis between AP and RBF, the upper frequency limit of AP lability (0.15 Hz) coincides with that of renal autoregulatory responses (20).

As previously reported in this model of the conscious SAD rat with renal denervation, the RBF was found to be well maintained during marked pressor episodes (20). Therefore, a higher pressure limit of RBF autoregulation was never detected. However, the pressor episodes allowed us to extend the range of AP describing the autoregulatory plateau and thus to improve its determination and that of PLL. Whether a higher pressure limit of RBF would be detectable in hypertensive SAD rats remains to be determined.

Acute administration of furosemide decreased both RBF and AP in SAD rats, whereas it decreased RBF and increased AP in intact rats. These observations confirm that sinoaortic baroreceptors are essential for maintaining AP after furosemide administration (15), probably through a mechanism involving sympathetic activation (19). The downward shift of the RBF autoregulatory plateau observed in SAD rats after furosemide points to tonic renal vasoconstriction. In vitro experiments in renal artery segments ruled out a possible direct vasoconstrictor effect of furosemide (14). Because in our experiments the kidney was denervated, a contribution of sympathetic nerves to renal vasoconstriction can be excluded. Moreover, as there was no indication of sympathoexcitation in SAD rats after furosemide (no significant change in heart rate, data not shown), the participation of increased levels of plasma catecholamines is unlikely, although it cannot be completely ruled out, especially because of denervation supersensitivity to alpha -adrenoceptor stimulation. Furosemide is known to increase renin secretion (5), and the renal vasoconstrictor action of furosemide in conscious rats has been shown to depend on the stimulation of angiotensin II receptors (14). Therefore, activation of the renin-angiotensin system seems the most likely explanation for the renal vasoconstriction observed in SAD rats after furosemide.

In addition to the downward shift of the RBF autoregulatory plateau, PLL was shifted rightward by ~10 mmHg. A similar value for PLL was revealed in intact rats after furosemide, suggesting that the SAD procedure did not alter the effect of furosemide on RBF autoregulation. An impairment of RBF autoregulation after furosemide has been previously reported in conscious dogs by using stepwise AP reductions from spontaneous AP (16, 25, 26). However, in these experiments, a new value for PLL could not be estimated, because an autoregulatory plateau could not be determined. In the SAD rats in the present study, the rightward shift of PLL after furosemide did not parallel the mean change in AP and therefore cannot be regarded as a classic pressure-resetting phenomenon. Rather, this observation suggests that the TGF mechanism contributes to autoregulatory efficiency and cooperates with the myogenic mechanism in setting PLL. Such an interaction between the TGF and myogenic mechanisms has been demonstrated in the in vitro blood-perfused juxtamedullary nephron preparation in response to step increases in renal perfusion pressure (23). One possible confounding factor in the present study is the activation of the renin-angiotensin system, which most probably occurred after furosemide administration, as discussed above. It has been reported in anesthetized rats that, after prolonged AP reduction, PLL was shifted toward lower AP values, an effect no longer observed after blockade of the renin-angiotensin system (6). Furthermore, clamping angiotensin II at a low level also induced a leftward shift of PLL (21). The authors suggested that potentiation of the TGF mechanism by angiotensin II might be responsible for the resetting of PLL. Our observation of a rightward shift of PLL in furosemide-treated SAD rats supports the view that the integrity of the TGF mechanism is required for angiotensin II to shift PLL leftward. A quantitative evaluation of the role played by angiotensin II in PLL resetting after furosemide would require blockage of the renin-angiotensin system and restoration of RBF by the infusion of angiotensin II. Whatever its mechanism, the furosemide-induced rightward shift of PLL, together with the mean decrease in AP, contributed to increase the percentage of AP values below PLL, which in turn contributed to increase the overall RBF variability in SAD rats.


    ACKNOWLEDGEMENTS

The authors are grateful to Dr. Jean-Marie Cottet-Emard for performing norepinephrine measurements.


    FOOTNOTES

S. L. S. Pires was supported by a scholarship from the Brazilian Coordenação de Aperfeiçoamento de Pessoal de Nível Superior and French Comité d'Evaluation de la Coopération Universitaire avec le Brésil.

Address for reprint requests and other correspondence: C. Barrès, Faculté de Pharmacie, 8 Ave. Rockefeller, 69373 Lyon Cedex 08, France (E-mail: barres{at}univ-lyon1.fr).

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.

First published August 8, 2001; 10.1152/ajprenal.00186.2001

Received 18 June 2001; accepted in final form 1 August 2001.


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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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