Inhibition of proximal tubular fluid absorption by nitric oxide and atrial natriuretic peptide in rat kidney

Eveline Eitle, Siriphun Hiranyachattada, Hui Wang, and Peter J. Harris

Department of Physiology, The University of Melbourne, Parkville, Victoria 3052, Australia

    ABSTRACT
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Abstract
Introduction
Methods
Results
Discussion
References

Atrial natriuretic factor (ANF) and nitric oxide (NO) stimulate production of guanosine 3',5'-cyclic monophosphate (cGMP) and are natriuretic. Split-drop micropuncture was performed on anesthetized rats to determine the effects of ANF and the NO donor sodium nitroprusside (SNP) on proximal tubular fluid absorption rate (Jva). Compared with control solutions, SNP (10-4 M) decreased Jva by 23% when administered luminally and by 35% when added to the peritubular perfusate. Stimulation of fluid uptake by luminal angiotensin II (ANG II; 10-9 M) was abolished by SNP (10-4 and 10-6 M). In proximal tubule suspensions, ANF (10-6 M) increased cGMP concentration to 143%, whereas SNP (10-6, 10-5, 10-4, 10-3 M) raised cGMP to 231, 594, 687, and 880%, respectively. S-nitroso-N-acetylpenicillamine (SNAP) also raised cGMP concentrations with similar dose-response relations. These studies demonstrate inhibition by luminal and peritubular NO of basal and ANG II-stimulated proximal fluid absorption in vivo. The ability of SNP to inhibit basal fluid uptake whereas ANF only affected ANG II-stimulated transport may be because of production of higher concentrations of cGMP by SNP.

guanosine 3',5'-cyclic monophosphate; guanylyl cyclase; angiotensin II; sodium nitroprusside; S-nitroso-N-acetylpenicillamine; renal micropuncture

    INTRODUCTION
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Abstract
Introduction
Methods
Results
Discussion
References

ATRIAL NATRIURETIC FACTOR (ANF) and nitric oxide (NO) exert potent effects on renal blood flow, glomerular hemodynamics, and sodium excretion by actions mediated by the second messenger guanosine 3',5'-cyclic monophosphate (cGMP) (1, 5, 15, 16, 18). In the rat proximal convoluted tubule in vivo, ANF has been shown to affect proximal tubular fluid absorption by inhibiting the stimulatory action of low concentrations of angiotensin II (ANG II) (12), whereas ANF alone had no effect on fluid absorption. Garvin (8) reported similar findings using perfused isolated rat proximal straight tubules and, in addition, demonstrated inhibition of ANG II-stimulated fluid transport by dibutyryl cGMP.

The effect of NO on proximal tubular Na+ transport has been addressed by several studies but remains controversial. Inhibition of NO decreased fractional lithium excretion (1, 22), indicating that NO reduces Na+ reabsorption, whereas other workers have reported that NO synthase inhibition reduced proximal Na+ transport and concluded that NO stimulates proximal reabsorption. More recently, Roczniak and Burns (25) have demonstrated that NO donors induce stimulation of soluble guanylyl cyclase, production of cGMP, and inhibition of an amiloride-sensitive Na+/H+ exchanger in rabbit proximal tubules and primary cell cultures.

The presence of the guanylyl cyclase-coupled ANF receptor in proximal tubules is indicated by microlocalization of specific mRNA for this receptor (29) and by our observation that ANF raises intracellular cGMP concentration (6) in these cells. In addition, many cells contain a cytosolic NO-sensitive guanylyl cyclase, but, although mRNA for subunits of soluble guanylyl cyclase has been detected in the interlobular artery as well as afferent and collecting duct arterioles (14), mRNA for this enzyme has not yet been detected in proximal tubules. Functional evidence for the activity of soluble guanylyl cyclase in these cells is provided by Roczniak and Burns (25), who found that a specific inhibitor of this enzyme attenuated the stimulation of cGMP production by NO.

We determined the effects on cGMP concentrations of addition of ANF, sodium nitroprusside (SNP), and S-nitroso-N-acetylpenicillamine (SNAP) to freshly isolated rat proximal tubules and, in split-droplet micropuncture experiments, investigated the effects of luminal or peritubular addition of SNP on proximal tubular fluid absorption. The results demonstrate that NO stimulates cGMP production with a maximum response greater than that achieved with ANF. The NO donor SNP (10-4 M) at a concentration which stimulates cGMP levels 4.2-fold compared with ANF (10-6 M) inhibited ANG II-stimulated fluid uptake and, in contrast to ANF (10-6 M), also reduced basal unstimulated rates of fluid absorption. However, SNP (10-6 M) at a concentration that raised cGMP to a similar level as ANF (10-6 M) did not affect basal rates of fluid absorption but, like ANF, inhibited ANG II-stimulated fluid uptake.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Micropuncture. Adult male Sprague-Dawley rats were anesthetized with Inactin (110 mg/kg ip) and infused intravenously with 0.9% NaCl at 1.6 ml · h-1 · 100 g body wt-1. The left kidney was prepared for micropuncture (11), and, after an equilibration period of 1-2 h, shrinking split-drop microperfusion was performed in midproximal convoluted tubule segments (S2) visible on the kidney surface. Sudan Black-stained castor oil was first introduced into a proximal tubule from one barrel of a double-barreled micropipette. An artificial tubular fluid solution (145 mM NaCl, 5 mM NaHCO3, 5 mM KCl, and 1.5 mM CaCl2) was then injected from the other barrel to split the oil column. The rate of shrinking of the split-drop was determined by digital image analysis of the positions of the oil-water menisci in successive video frames captured at 1-s intervals (11). In a group of seven rats, proximal fluid uptake rate per unit surface area of epithelium (Jva) was determined in three to five tubules, and a mean value was calculated. Fluid absorption rate was then determined in a further three or more tubules using intratubular fluid containing the NO donor SNP (10-6 or 10-4 M). In two separate groups of 10 rats, fluid absorption during perfusion with control solution was compared with fluid uptake during perfusion with a similar fluid containing ANG II (10-9 M) and then with fluid containing ANG II (10-9 M) and SNP (10-4 M) or SNP (10-6 M) together.

Perfusion of the peritubular capillaries surrounding the split-drop was performed to investigate the effect on proximal fluid uptake of peritubular delivery of NO. Peritubular capillaries were perfused with a control solution similar to plasma but without addition of protein and was introduced using gas (95% O2-5% CO2) applied to a micropipette at a pressure sufficient to clear the blood from all capillaries adjacent to the split-drop. In a group of five animals, average values for fluid uptake rates were obtained in three to five tubules during peritubular perfusion with control fluid and then in a further three to five tubules during perfusion with a similar fluid containing SNP (10-4 M).

Preparation of proximal tubule suspensions. Suspensions of renal proximal tubules were prepared using a modification of the procedures described by Wrenn et al. (31) and Schlatter et al. (27). Seven Sprague-Dawley rats (200-230 g; Austin Hospital, Melbourne, Australia) were anesthetized with Nembutal (phenobarbitone sodium, 6-10 mg/100 g body wt ip; Boehringer Fugelliem, Artarmon, New South Wales, Australia). A cannula (0.86 mm ID; 1.52 mm OD) was inserted into the abdominal aorta and used to perfuse both kidneys simultaneously with 40-60 ml of an ice-cold isotonic buffer (pH 7.5) containing (in mM) 130 NaCl, 5 NaHCO3, 1.6 Na2HPO4, 0.4 NaH2PO4, 1.3 CaCl2, 5 KCl, 1 MgSO4, 10 sodium acetate, 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 3 glucose, and 2 glycine. The kidneys were then perfused with a further 40-60 ml of this solution containing ~1% (wt/vol) magnetic iron oxide particles (carbonyl iron, Sigma). This suspension was filtered before use, first through a 60-µm and then through a 10-µm nylon mesh. The kidneys were then removed and decapsulated, and the cortex was carefully separated and chopped into small pieces with a scalpel. The tissue was digested at 37°C for 20 min in a horizontal shaking waterbath (50 revolutions/min) in the above buffer containing 1 mg/ml collagenase (type 4, Worthington Biochemical) and 2 IU/ml protease (Pronase E, Sigma Chemical). The resulting suspension was filtered once through a 200-µm mesh sieve and washed by sedimentation in a 200-ml beaker. The suspension of tubules and glomeruli was then placed in a 10-ml tube and passed four to six times through a magnetic field to allow separation of small vessels and glomeruli containing trapped iron oxide. The remaining tissue, consisting mainly of proximal tubules, was resuspended in cold (4°C) buffer and examined under dark-field illumination using a stereo microscope. Contaminating vascular tissue and glomeruli were separated using fine needles and removed by aspiration.

Treatment of isolated proximal tubules with ANF and SNP. Suspensions of proximal tubules were stored on ice until use. Aliquots (90 µl containing 200-700 µg protein) of suspension were incubated in polypropylene tubes for 3 min at 37°C in a horizontal shaking waterbath. ANF (Auspep, Victoria, Australia), SNP (May and Baker), or SNAP (Sapphire Bioscience, New South Wales, Australia) was dissolved in HEPES buffer (as described above), and 10 µl were added to experimental tubes to give final concentrations of ANF, SNP, or SNAP as indicated. A similar volume of buffer was added to control tubes. The SNP and SNAP solutions were made up immediately before use. The suspension was mixed by manual agitation and reincubated for 1 min at 37°C in the waterbath. The reaction was stopped by adding 100 µl ice-cold 10% perchloric acid. The tubes were placed on ice for 15-30 min and then centrifuged for 3 min at 10,000 g in a microcentrifuge. Aliquots (190 µl) of the supernatant were placed in new tubes for neutralization as described by Sharps and McCarl (28). Briefly, samples were brought to a total volume of 600 µl by adding distilled water, vigorously mixed with 700 µl of a mixture (1:1, vol/vol) of tri-n-octylamine (Sigma Chemical) and 1,1,2-trichloro-trifluoroethane (Sigma Chemical), and then centrifuged at 10,000 g in a microcentrifuge for 1 min. A portion (300 µl) of the top layer was carefully removed, freeze dried, and stored at -20°C while awaiting assay for cGMP.

Measurement of cGMP. cGMP concentration in cell extracts was determined by a specific radioimmunoassay (19). Acetylated standards and sample extracts were prepared using synthetic cGMP (Sigma Chemical) as described by Marley et al. (20). Protein concentrations were determined according to the method of Lowry et al. (17).

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Effect of luminal addition of SNP. The effect on proximal tubular fluid absorption of luminal addition of SNP is shown in Fig. 1. At a concentration of 10-6 M, SNP had no effect on net fluid uptake, but at 10-4 M, SNP significantly reduced mean Jva by 23% compared with the uptake rate measured using control tubular fluid alone (1.89 ± 0.16 vs. 2.53 ± 0.24 × 10-4 mm3 · mm-2 · s-1).


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Fig. 1.   Graph representing mean values for proximal tubular fluid absorption rate (Jva) measured by shrinking split-drop micropuncture during luminal perfusion with control tubular fluid (TF) and sodium nitroprusside (SNP; 10-4 and 10-6 M). Data represent means ± SE of 2 or 3 tubules per treatment per animal. * P < 0.05 vs. control, paired t-test (n = 7).

Effect of peritubular perfusion with SNP. As shown in Fig. 2, addition of SNP (10-4 M) to the peritubular capillary perfusate resulted in a decrease in mean Jva by 35% compared with perfusion with control solution (1.71 ± 0.11 vs. 1.11 ± 0.22 × 10-4 mm3 · mm-2 · s-1).


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Fig. 2.   Graph representing mean values for proximal tubular fluid absorption rate (Jva) measured by shrinking split-drop micropuncture during peritubular capillary perfusion with control perfusion fluid (PTF) or PTF containing SNP (10-4 M). Data represent means ± SE of 2 or 3 tubules per treatment per animal. * P < 0.05 vs. control, paired t-test (n = 5).

Effect of SNP on ANG II-stimulated fluid transport. As shown in Fig. 3, in six of nine animals, addition of ANG II (10-9 M) to the intratubular solution increased the mean rate of fluid uptake by 34% compared with control (3.03 ± 0.13 vs. 2.26 ± 0.16 × 10-4 mm3 · mm-2 · s-1). When ANG II (10-9 M) and SNP (10-4 M) were added together to the intratubular solution fluid, absorption rate was reduced to the control level (2.41 ± 0.24 × 10-4 mm3 · mm-2 · s-1). In the remaining three animals in this group, no response to ANG II was observed, and these animals were not included in the subsequent analysis.


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Fig. 3.   Graph showing proximal tubular fluid uptake during luminal perfusion with control tubular fluid (TF), angiotensin II (ANG II; 10-9 M), or ANG II (10-9 M) plus SNP (10-4 M). Data represent means ± SE of 2 or 3 tubules per treatment per animal. + P < 0.05 vs. control. * P < 0.05 vs. ANG II (10-9 M), paired t-test (n = 6).

In a similar set of experiments shown in Fig. 4, in 6 of 10 animals, addition of ANG II (10-9 M) to the intratubular solution increased the mean rate of fluid uptake by 20% compared with control (2.74 ± 0.10 vs. 2.28 ± 0.13 × 10-4 mm3 · mm-2 · s-1). When ANG II (10-9 M) and SNP (10-6 M) were added together to the intratubular solution fluid, absorption rate was reduced to the control level (2.19 ± 0.16 × 10-4 mm3 · mm-2 · s-1). In the remaining four animals in this group, no response to ANG II was observed, and these animals were not included in the subsequent analysis.


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Fig. 4.   Graph showing proximal tubular fluid uptake during luminal perfusion with control tubular fluid (TF), ANG II (10-9 M), or ANG II (10-9 M) plus SNP (10-6 M). Data represent means ± SE of 2 or 3 tubules per treatment per animal. + P < 0.05 vs. control. * P < 0.05 vs. ANG II (10-9 M), paired t-test (n = 6).

Effect of ANF and SNP on cGMP levels in proximal tubule suspensions. Incubation of proximal tubules with ANF (10-6 M) for 1 min resulted in an increase (1.4-fold) of cGMP concentration from 37 ± 4 to 53 ± 6 fmol/mg protein (Fig. 5). SNP increased accumulation of cGMP at concentrations of 10-6, 10-5, 10-4, and 10-3 M from 35 ± 1.4 to 81 ± 12, 208 ± 33, 241 ± 41, and 308 ± 66 fmol/mg protein, respectively (Fig. 6). SNAP increased accumulation of cGMP at concentrations of 10-5, 10-4, 10-3, and 10-2 M from 37 ± 1.5 to 68 ± 13, 238 ± 102, 337 ± 18, and 377 ± 110 fmol/mg protein, respectively (Fig. 7). Higher concentrations of ANF (10-5 M) failed to elicit any further increases in cGMP levels in tubules from Wistar-Kyoto rats, indicating that the response obtained was maximal.


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Fig. 5.   Graph showing cGMP concentrations in proximal tubule suspensions in response to a 1-min incubation with control buffer (con) or atrial natriuretic factor (ANF; 10-6 M). Data shown represent means ± SE of samples (measured in triplicate) from 7 animals. * P < 0.01 vs. control, paired t-test.


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Fig. 6.   Graph showing cGMP concentrations in proximal tubule suspensions in response to a 1-min incubation with control buffer or various concentrations of SNP (10-7, 10-6, 10-5, 10-4, and 10-3 M). Data shown represent means ± SE of samples (measured in triplicate) from 8 animals. * P < 0.01, ** P < 0.001 vs. control, paired t-test.


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Fig. 7.   Graph showing cGMP concentrations in proximal tubule suspensions in response to a 1-min incubation with control buffer or various concentrations of S-nitroso-N-acetylpenicillamine (SNAP; 10-6, 10-5, 10-4, 10-3, and 10-2 M). Data shown represent means ± SE of samples (measured in triplicate) from 8 animals. * P < 0.05, ** P < 0.001 vs. control, paired t-test.

    DISCUSSION
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Abstract
Introduction
Methods
Results
Discussion
References

The data presented demonstrate that NO acts to inhibit sodium and water reabsorption in the rat proximal convoluted tubule. This action was observed when the NO donor SNP at 10-4 M, a concentration that raised cGMP about sevenfold above control levels, was added to the luminal fluid and when SNP (10-4 M) was perfused into the peritubular capillaries. SNP at 10-6 M, a concentration which raised cGMP 2.3-fold, added to the luminal fluid had no effect on basal sodium and water reabsorption, but luminal SNP at 10-4 and 10-6 M abolished the stimulatory action of intratubular ANG II on fluid uptake. SNP and ANF both increased cGMP concentrations in isolated proximal tubules, but the maximum response observed with SNP was approximately six times greater than with ANF.

Previous reports have suggested that the proximal tubule is a site of action for NO (1, 22). It has also been demonstrated in primary cultures of rabbit proximal tubule cells that NO donors inhibit amiloride-sensitive 22Na+ uptake used as an indicator of Na+/H+ exchanger activity (25). Our work confirms the presence of functional NO-sensitive guanylyl cyclase in rat proximal tubules and shows that, in vivo, NO acts to inhibit transepithelial Na+ and water absorption.

The NO donor SNP was effective in reducing net fluid absorption whether added to the luminal or peritubular sides of the tubular epithelium. Evidence based on the detection of mRNA for various isoforms of nitric oxide synthase (NOS) in rat kidney indicates that NO could be produced in endothelial cells adjacent to the proximal tubule (21) or in the proximal tubule cells themselves (30). NO produced by endothelial NO synthase could diffuse into the epithelial cells to act on the soluble guanylyl cyclase, or locally produced NO might act in an autocrine manner to affect production of cGMP.

Administration of ANF resulted in increased intracellular cGMP levels in isolated proximal tubules (Fig. 4). The NO donors SNP and SNAP increased cGMP levels in a dose-dependent manner (Figs. 6 and 7). The data reported here indicate that NO is considerably more effective than ANF in raising cGMP concentration. Our results do not provide an explanation for this difference, but it is likely that the data reflect the relative activity or abundance of the soluble guanylyl cyclase activated by NO compared with the membrane-bound guanylyl cyclase ANF receptor.

The cellular mechanisms by which cGMP might act as a common messenger for the actions of both NO and ANF are not directly addressed by our experiments. However, some insight into these mechanisms is provided by the ability of NO to inhibit ANG II-stimulated fluid absorption (Figs. 3 and 4). We have previously reported that ANF, when added to the peritubular fluid, inhibited ANG II-stimulated fluid transport in the rat proximal convoluted tubule, although ANF alone had no effect (12). Garvin (8) confirmed these findings in perfused, isolated tubules and demonstrated that ANG II-stimulated transport was also inhibited by the membrane-permeant analog dibutyryl cGMP. In the present experiments, in animals in which proximal fluid uptake in split-drops was stimulated by addition of ANG II to the intratubular fluid, absorption rate returned to control levels when SNP was added to the luminal fluid together with ANG II. We infer that NO diffuses into proximal tubule cells and stimulates soluble guanylyl cyclase, resulting in accumulation of cGMP. This nucleotide then acts to modulate the cellular processes involved in the stimulatory action of ANG II on transepithelial Na+ transport, resulting in restoration of fluid transport rate to the control level. Variation in proximal tubule responsiveness to ANG II has also been reported by Coppola and Fromter (4), who applied a concentration of 10-11 M to the bathing solution of perfused, isolated rabbit proximal tubules. In 85% of tubules tested, there was a small depolarization, whereas the remaining 15% responded with a small hyperpolarization. The cause of these variations in responsiveness remains unclear, but it is known that ANG II is produced within proximal tubule cells and secreted into the lumen (2) where it can affect the rate of fluid uptake (13). Differences in the rate of secretion of locally produced ANG II might be responsible for variations in the basal rate of sodium reabsorption and for differences in responsiveness to addition of exogenous peptide.

Modulation of proximal tubular sodium transport by ANF or cGMP is thought to involve cGMP-dependent phosphorylation of a target protein, since KT-5823, a cGMP-dependent protein kinase inhibitor, blocked the action of ANF on ANG II-stimulated fluid absorption in the isolated perfused rat proximal tubule (7). Several other mechanisms have been implicated in the proximal actions of ANF, and these appear to be activated independently of stimulation by ANG II or any other hormone or norepinephrine. The majority of reports have supported the view that ANF alone does not affect proximal Na+ transport (8, 12), although Hammond et al. (10) demonstrated inhibition of Na+/H+ exchange and Na+-dependent Pi uptake in proximal brush-border membrane vesicles from rats pretreated by infusion of ANF.

ANF has also been shown to increase Ca2+-Mg2+-ATPase activity in basolateral membranes isolated from rat kidney, and its action on epithelial Na+ transport may involve altered intracellular Ca2+ homeostasis (26). Reddy et al. (24) found cell swelling in response to ANF in proximal tubule cells from rat kidneys examined using electron microprobe X-ray analysis and concluded that ANF, presumably acting through cGMP, inhibits the Na+ pump. A further mechanism involves a cGMP-activated Cl- channel found in cultured rat proximal convoluted tubule cells (23) that could mediate the action of ANF by allowing Cl- to leave the cells and thus reduce the lumen-positive driving force for Na+ reabsorption.

Although there is little evidence for a direct action of ANF acting alone to influence proximal tubular reabsorption, our experiments show that NO inhibited not only ANG II-stimulated transport (Fig. 3) but also reduced fluid uptake in the absence of peritubular ANG II (Fig. 2). The inhibitory effect of luminal addition of SNP on fluid uptake shown in Fig. 1 was observed under conditions of normal blood perfusion through the peritubular capillaries, and it is likely that this blood contained ANG II at a concentration expected to exert a stimulatory action on fluid transport (32). In support of a direct action of NO on proximal tubular transport, Roczniak and Burns (25) found that NO donors inhibit Na+/H+ exchange activity determined by amiloride-sensitive 22Na+ uptake in primary cultures of rabbit proximal tubules, and Guzman et al. (9) have reported an inhibitory action of NO on the Na+-K+-ATPase in cultured mouse proximal tubule cells. These actions of NO appear to be dependent at least in part on the generation of cGMP but may also involve the production of peroxynitrite radicals or activation of other cGMP-independent pathways that might act to modulate transporter activities.

A recent study by Chevalier et al. (3) on LLC-PK1 cells suggests that during treatment with an NO donor, cGMP is transported out of proximal tubule cells by a probenecid-sensitive organic anion transporter and acts in an autocrine fashion to alter transepithelial Na+ transport. Our experiments do not enable us to identify an action of extracellular cGMP in response to NO, but neither do they exclude such an action. Perfusion of peritubular capillaries during in vivo micropuncture experiments provides a means for delivery of known concentrations of hormones and for exclusion of circulating factors. However, cGMP extruded from the cells into the interstitial fluid or into the lumen would still be available to influence cellular function.

Our finding that ANF and SNP (10-6 M) inhibit only ANG II-stimulated transport, whereas SNP (10-4 M) also affects fluid uptake in the absence of any apparent stimulation by ANG II may be because of the different levels of cGMP production. Although ANF raised cGMP in our preparation of proximal tubule suspensions only 1.4-fold and SNP (10-6 M) 2.3-fold above control levels in 1 min, SNP (10-4 M) raised cGMP 6.5-fold under the same conditions. The concentration of cGMP reached within or around the proximal tubule cell may therefore determine which of the various regulatory pathways involved in control of transepithelial sodium transport are influenced by delivery of extracellular modulators such as ANF and NO.

    ACKNOWLEDGEMENTS

We are grateful to Dr. Philip Marley for the supply of radiolabeled nucleotide and antibody for the cGMP assay.

    FOOTNOTES

This work was supported by the National Health and Medical Research Council of Australia.

Address reprint requests to P. J. Harris.

Received 9 December 1996; accepted in final form 12 December 1997.

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Top
Abstract
Introduction
Methods
Results
Discussion
References

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AJP Cell Physiol 274(4):C1075-C1080
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