Department of Ophthalmology and Visual Sciences and Department of Pharmacology and Toxicology, University of Louisville, School of Medicine, Louisville, Kentucky 40292
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ABSTRACT |
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Angiotensin (ANG) II receptors have been reported in the nonpigmented ciliary epithelium (NPE) of the eye. In cultured NPE, we found ANG II caused a dose-dependent rise of cytoplasmic sodium. The sodium increase was inhibited by the AT1-AT2 receptor antagonist saralasin (IC50 = 3.7 nM) and the AT1 antagonist losartan (IC50 = 0.6 nM) but not by the AT2 antagonist PD-123319. ANG II also caused a dose-dependent increase in the rate of ouabain-sensitive 86Rb uptake. The ANG II-induced cell sodium increase and 86Rb uptake increase were reduced by dimethylamiloride (DMA; 10 µM). On the basis of this finding, we propose that Na+/H+ exchange is stimulated by ANG II. Simultaneously, ANG II appears to inhibit H+-ATPase-mediated proton export. Thus Ang II (10 nM) did not alter the baseline cytoplasmic pH (pHi) but reduced pHi in cells that were also exposed to 10 µM DMA. Consistent with the notion of H+-ATPase inhibition in ANG II-treated NPE, bafilomycin A1 (100 nM) (BAF) and ANG II were both observed to suppress the pHi increase that occurs upon exposure to a mixture of epinephrine (1 µM) and acetylcholine (10 µM) and the pHi increase elicited by depolarization. In ATP hydrolysis measurements, H+-ATPase activity (bafilomycin A1-sensitive ATP hydrolysis) was reduced significantly in cells that had been pretreated 10 min with 10 nM ANG II. In summary, these studies suggest that ANG II causes H+-ATPase inhibition and an increase of cell sodium due to activation of Na+/H+ exchange.
cytoplasmic pH; H+-ATPase; bafilomycin A1
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INTRODUCTION |
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ANGIOTENSIN-CONVERTING ENZYME inhibitors and angiotensin (ANG) II receptor antagonists are able to cause a reduction of intraocular pressure (1, 8, 9, 23), and this has raised interest in the possible effects of ANG II on the ciliary epithelium bilayer, the tissue responsible for aqueous humor secretion. In the rabbit eye, ANG II receptors have been shown to be localized in the ciliary epithelium as judged by radioligand binding studies (16). Similar evidence for ANG II receptor expression has been reported in human nonpigmented ciliary epithelium (NPE) grown in culture (16), and the exposure of cultured human NPE to ANG II was observed to increase cytoplasmic calcium concentration (14). In situ hybridization showed mRNA for both AT1 and AT2 receptor subtypes in rat ciliary body (35).
The ability of ANG II to alter sodium transport has been extensively documented. In several tissues, Na+-K+-ATPase is stimulated following AT receptor activation (2, 20, 24). In the present study, we examined the influence of ANG II on cytoplasmic sodium in cultured rabbit NPE. An increase in the rate of Na+-K+-ATPase-mediated 86Rb transport observed in ANG II-treated NPE cells appeared to be the result of a rise of cytoplasmic sodium concentration. In the kidney, ANG II is also reported to change the activity of H+-ATPase-mediated proton export (15, 31, 32). Because Wax and coworkers (34) suggested that alteration in the activity of a plasma membrane-localized H+-ATPase might change NPE function, the influence of ANG II on cytoplasmic pH (pHi) responses was also examined. Here we present the results from pHi studies that suggest that H+- ATPase is inhibited in ANG II-treated cells.
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MATERIALS AND METHODS |
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Chemicals. 2',7'-Bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-AM, fura 2-AM, sodium-binding benzofuran isophthalate (SBFI)-AM, and Pluronic F-127 were obtained from Molecular Probes (Eugene, OR). All other chemicals were purchased from Sigma (St. Louis, MO). Materials insoluble in water were dissolved in minimum volume of dimethyl sulfoxide (DMSO), 20% Pluronic F-127 in DMSO, or ethanol (<0.1% final concentration). An equal amount of DMSO or ethanol was added to control solutions.
Cell culture. The NPE cell line used in this study was a kind gift from Dr. M. Coca-Prados (Yale University, New Haven, CT). The cells were derived from SV40 virus-transformed rabbit nonpigmented ciliary epithelium and have been used previously in studies of pHi regulation and active Na+-K+ transport (10, 12, 13). The cells were grown under a humidified atmosphere of 5% CO2-95% air at 37°C on 35-mm petri dishes in Dulbecco's modified Eagle's medium (GIBCO, Gaithersburg, MD) supplemented with 10% fetal bovine serum, 100 U/ml penicillin, and 100 µg/ml streptomycin. The culture medium was changed every 2-3 days, and the cells were used before confluence.
Measurement of cell sodium by atomic absorption spectrophotometry. Cell monolayers were washed with ice-cold isotonic magnesium chloride solution (100 mM MgCl2, adjusted to pH 7.4 with Tris base). The magnesium chloride solution was then removed, and the cells were lysed by adding 200 µl of 30% nitric acid to each well. After this, 1.8 ml of deionized water was added to each well, and the sodium content of the diluted cell lysates was measured by using an atomic absorption spectrophotometer (Perkin-Elmer, Norwalk, CT) at a wavelength of 566.5 nm.
Measurement of pHi by digital fluorescence microscopy. The fluorescent pH-sensitive dye BCECF was used to measure pHi in cells that were continuously superfused at a rate of 1 ml/min with Krebs solution with the following composition: 119 mM NaCl, 4.7 mM KCl, 1.2 mM KH2PO4, 25 mM NaHCO3, 2.5 mM CaCl2, 1 mM MgCl2, and 5.5 mM glucose at pH 7.4, equilibrated with 5% CO2-95% air. Potassium-rich Krebs solution was prepared by increasing the concentration of KCl to 80 mM and decreasing the concentration of NaCl by 80 mM. To load the cells with fluorescent dye, the cells were incubated for 30 min in Krebs solution containing 10 µM BCECF-AM under a humidified 5% CO2-95% air at 37°C. After being loaded, the cells were washed three times with Krebs solution, and the petri dish was mounted on the stage of a fluorescence microscope (Zeiss, Thornwood, NY) equipped with a digital imaging system (Attofluor Instruments, Rockville, MD). The microscope stage was warmed to 37°C by a water jacket, and a flow-through temperature controller (Warner Instrument, Hamden, CT) was used to set the temperature of the incoming superfusate to 37°C. The fluorescence intensity of BCECF was measured by using an emission wavelength of 520 nm and alternating dual-excitation wavelengths of 460 and 488 nm. The relationship between pHi and the ratio of fluorescence intensity at 460 nm to that at 488 nm was calibrated at the end of each experiment. Cells were first exposed to a potassium-rich buffer containing 10 µM nigericin, which mediates K+/H+ exchange and thereby equilibrates the extracellular pH and intracellular pH. The potassium-rich buffer contained 110 mM KCl, 20 mM NaCl, and a 20 mM buffer selected to control pH. 2-(N-morpholino)ethanesulfonic acid (MES; pKa = 6.1) was used to set pH in the range 6.0-6.5; piperazine-N,N'-bis(2-ethanesulfonic acid) (PIPES; pKa = 6.8) was used to set pH at 7.0; N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES; pKa = 7.5) was used to set pH at 7.4; and N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS; pKa = 8.4) was used to set pH at 8.4.
Measurement of cytoplasmic sodium concentration by digital fluorescence microscopy. The fluorescent dye SBFI was used to measure cytoplasmic sodium concentration. SBFI-AM was dissolved in 20% Pluronic F-127 in DMSO and added to the Dulbecco's modified Eagle's cell culture medium for 3-4 h at a final concentration of 10 µM SBFI-AM, <0.1% Pluronic F-127, and <0.5% DMSO. The methodology was similar to that described for pHi measurements. The alternating excitation wavelengths were 340 and 380 nm. To calibrate the signal at the end of each experiment, the cells were permeablized by exposure to Krebs solution containing 10 µM nigericin, 5 µM monensin, and 5 µM gramicidin and a range of sodium concentrations. The fluorescence ratio signal was thus measured in the permeablized cells equilibrated to different external sodium concentrations.
Measurement of cytoplasmic calcium by digital fluorescence microscopy. Cytoplasmic calcium concentration was measured using the calcium-sensitive dye fura 2 with alternating excitation wavelengths of 334 and 380 nm. The methodology was similar to that described for pHi measurements. The relationship between cytoplasmic calcium and the ratio of fluorescence intensity at 334 nm to that at 380 nm was calibrated at the end of each experiment by first adding 1 µM ionomycin to the superfusate to permit calcium equilibration with the external solution to obtain the maximum fluorescence ratio. EGTA (30 mM) was then added to the superfusate in the continued presence of ionomycin to obtain minimum fluorescence ratio.
Measurement of H+-ATPase activity. H+-ATPase activity was determined by using a modification of the technique described by Tojo and coworkers (30) in which ATP hydrolysis is coupled to the oxidation of NADH. Before the ATP hydrolysis stage of the experiment, cell monolayers were incubated in Krebs solution, and some cells were also exposed to 10 nM ANG II for 10 min. After this, the Krebs solution was replaced by 100 µl of assay buffer containing 100 mM NaCl, 66.7 mM NH4Cl, 3.7 mM MgCl2, 2 mM CaCl2, 50 mM imidazole, 5 mM glucose, and 0.05% bovine serum albumin. The samples were immediately frozen for 30 min and then thawed to permeabilize the cells. Each sample then received 100 µl of reaction solution containing 100 mM NaCl, 66.7 mM NH4Cl, 50 mM imidazole, 3.7 nM MgCl2, 7.5 mM sodium azide, 3.3 mM disodium-ATP, 1 mM EDTA, 12 mM ouabain, 0.6 mM phosphoenolpyruvate, and 9.6 U/ml pyruvate kinase. Half the samples also received bafilomycin A1 added to a final concentration of 100 nM. Bafilomycin A1 is a specific inhibitor of H+-ATPase activity (4). The samples were incubated at 37°C in a shaking water bath for 40 min. At the end of the ATP hydrolysis period, 1 ml of a solution containing 2.5 mM NADH and 6 U/ml lactate dehydrogenase in 0.1 N potassium phosphate buffer was added for 40 min, and then 150 µl of 30% ice-cold trichloroacetic acid were added. The supernatant was then removed, and the amount of NADH oxidized by pyruvate was measured by using a fluorimeter to quantify the decrease in emission at 460 nm with an excitation wavelength of 340 nm. The cells remaining in each well were digested in 0.5 N NaOH, and an aliquot was used to measure protein by using a colormetric Bio-Rad assay (Bio-Rad, Hercules, CA). Because there is a 1:1 stoichiometric relationship between the amount of NADH oxidized and the amount of ADP generated as the result of ATP hydrolysis, H+-ATPase activity was calculated from the difference in the amount of NADH oxidized in the presence or absence of the H+-ATPase inhibitor bafilomycin A1 (100 nM). H+- ATPase activity is expressed as picomoles of ATP hydrolyzed per milligram of protein per minute.
Data analysis. Student's t-test was used for the statistical analysis. Values of P < 0.05 were considered significant.
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RESULTS |
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ANG II increases the cytoplasmic sodium concentration.
Cultured nonpigmented ciliary epithelial cells were preloaded with SBFI
and then exposed to ANG II at a concentration of 1 nM. A
progressive increase of cytoplasmic sodium concentration was observed
shortly after ANG II addition (Fig.
1A). In separate experiments,
the sodium content of NPE cell monolayers was measured by using atomic
absorption spectrophotometry. Cells were exposed for 30 min to ANG II
at concentrations ranging from 0.1 pM to 10 nM. A significantly
elevated sodium content was observed in cells exposed to ANG II at
concentrations of 10 pM or higher. The maximum observed increase in
sodium content occurred in cells exposed to 1 nM ANG II (Fig.
1B).
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Dimethylamiloride. In other tissues it has been suggested that Na+/H+ exchanger activity may be altered by ANG II. To examine the possible contribution of the Na+/H+ exchanger to the ANG II-induced increase of NPE sodium content, cells were exposed to ANG II in the presence of 10 µM dimethylamiloride (DMA), an inhibitor of Na+/H+ exchange (6) that is also known to inhibit epithelial sodium channels when used at higher concentrations (5, 33). In the presence of DMA, ANG II failed to elicit a significant increase of cell sodium content (Fig. 1B).
Involvement of ANG II receptors.
To test whether the mechanism involves activation of ANG II receptors,
some cells were exposed to ANG II in the presence of saralasin, an
antagonist for both AT1 and AT2 receptors.
Saralasin suppressed the sodium increase in ANG II-treated cells in a
dose-dependent manner (Fig.
2A). Based on a curve fit to
the data shown in Fig. 2A, the IC50 for
saralasin was 3.7 ± 0.7 nM. Losartan, an
AT1-selective receptor antagonist, also inhibited the
cytoplasmic sodium increase in ANG II-treated cells (Fig.
2B). The calculated IC50 for losartan was
0.57 ± 0.15 nM. In contrast, PD-123319 (100 µM), an
AT2 receptor antagonist, failed to prevent the rise of
sodium that followed ANG II exposure (Fig. 2C).
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Na+-K+-ATPase-mediated
sodium-potassium transport.
The ability of ANG II to cause an increase of cell sodium concentration
suggests that Na+-K+-ATPase-mediated ion
transport might be stimulated in cells exposed to ANG II. To test this,
ouabain-sensitive potassium uptake was measured as 86Rb
uptake in the cells treated with ANG II. In the presence of 10 nM ANG
II, the rate of 86Rb uptake was stimulated by ~40% (Fig.
3). In sharp contrast, ANG II failed to
increase the rate of 86Rb uptake in cells that were
simultaneously exposed to 10 µM DMA (Fig. 3).
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pHi.
Studies were conducted to examine the influence of ANG II on
pHi. Cells were preloaded with the pH-sensitive dye BCECF
before being exposed to 10 nM ANG II. The resting pH was 7.1 ± 0.14 (mean ± SE; n = 6 experiments). The addition
of ANG II failed to cause a detectable pH change (Fig.
4A). However, in the presence
of DMA, ANG II produced cytoplasmic acidification. Added alone, 10 µM
DMA reduced pHi from 7.09 ± 0.05 to a new stable
value of 6.77 ± 0.07 (Fig. 4B). Exposure of the cells
to 10 nM ANG II in the continued presence of DMA caused a further pH
reduction to 6.45 ± 0.04.
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Bafilomycin A1.
In a previous study, bafilomycin A1 was found to reduce
pHi in DMA-treated cells (12). The similarity
between the pH responses of DMA-treated cells to ANG II and bafilomycin
A1 suggests that H+-ATPase might be inhibited
when cells are exposed to ANG II. Consistent with this notion,
bafilomycin A1 and ANG II were both found to inhibit the
pHi increase that occurs when NPE cells are exposed to a
mixture of epinephrine and acetylcholine (Fig.
5, A and B). Similarly, ANG II and bafilomycin A1 both significantly
(P < 0.01) reduced the magnitude of the
pHi increase that occurs on cell depolarization by
potassium-rich solution; in control cells, exposure to 80 mM KCl for 5 min caused a pHi increase of 0.58 ± 0.12 pH unit,
whereas in the presence of ANG II (10 nM) or bafilomycin A1
(100 nM) the pH increase was 0.18 ± 0.11 or 0.15 ± 0.09, respectively (means ± SE; n = 6). Like ANG II,
bafilomycin A1 did not directly alter pHi (Fig.
5C). Moreover, pHi was also found to remain
stable when ANG II was added in the continued presence of bafilomycin A1 (Fig. 5C).
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H+-ATPase activity.
ATP hydrolysis measurements were conducted as a more direct way to
examine the potential influence of ANG II on H+-ATPase
activity. In control cells, H+-ATPase activity was
120.9 ± 19.2 pmol ATP hydrolyzed · mg
protein-1 · min-1 (means ± SE,
n = 12). H+-ATPase activity was reduced by
>50% in cells that had been exposed to 10 nM ANG II for 10 min before
the measurement of ATP hydrolysis (Fig.
7). Under the ATPase assay conditions,
Na+-K+-ATPase activity was fully inhibited
because of the addition of ouabain and the omission of potassium from
the assay solution. Mitochondrial ATPase activity was inhibited by the
inclusion of sodium azide in the assay solution, and calcium-activated
ATPases were inhibited by the inclusion of EDTA.
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DISCUSSION |
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ANG II changes sodium dynamics in many tissues, and here we show that it causes an increase in the cytoplasmic sodium concentration in cultured rabbit NPE. The rate of Na+-K+-ATPase-mediated 86Rb transport increases by ~40% in NPE cells exposed to ANG II. A similar stimulatory effect of ANG II on Na+-K+-ATPase has been reported in astrocytes (20) and kidney (24). In cultured NPE, the mechanism responsible for the ANG II-induced stimulation of active Na+-K+ transport appears to involve the increase of cytoplasmic sodium concentration that occurs in ANG II-treated cells because prevention of the sodium increase abolished the stimulation of 86Rb uptake. The ability of saralasin and losartan but not PD-123319 to suppress the sodium increase suggests that the mechanism involves activation of AT1 receptors.
The ability of DMA to suppress both the rise of sodium and the stimulation of ouabain-sensitive 86Rb uptake in ANG II-treated cells suggests that the increase of Na+-K+-ATPase-mediated 86Rb transport is the result of an elevation in cytoplasmic sodium concentration. However, exposure of the cells to ANG II has been observed to cause an increase of cytoplasmic calcium concentration in cultured NPE (14), and an increase of cytoplasmic calcium concentration has been found to stimulate Na+-K+-ATPase-mediated active Na+-K+ transport in NPE and other tissues (19, 36). Elevated cytoplasmic calcium concentration has also been observed to cause activation of H+-ATPase in cultured NPE (13). However, there is no evidence to suggest that H+-ATPase activation occurs in ANG II-treated cells. Instead, the response to ANG II is consistent with H+-ATPase inhibition together with a concomitant activation of Na+/H+ exchange.
The increase in cytoplasmic sodium caused by ANG II was inhibited by DMA at a concentration of 10 µM, which is very close to the IC50 of 7 µM reported for inhibition of Na+/H+ exchange in adrenal glomerulosa cells by DMA (7). This suggests that stimulation of Na+/H+ exchange occurs in ANG II-treated cultured NPE. However, we cannot rule out the possibility that some sodium enters the ANG II-treated NPE via sodium channels because, although a 10 µM concentration of DMA is insufficient to inhibit sodium channels in lung airway epithelium (33), DMA at a higher concentration elicits detectable sodium channel blockade in cortical collecting duct cells (5). It should also be noted that the family of Na+/H+ exchangers contains six isoforms (22). The distribution of Na+/H+ exchanger isoforms can be quite different in different tissues (17, 22, 25). The sensitivity of different Na+/H+ exchanger isoforms to DMA varies considerably, and the IC50 for DMA can be much lower in some cell types (17, 25). The pattern of Na+/H+ exchanger isoforms expression is not known for the cultured rabbit NPE cells used in the present study. For cultured human NPE, Civan et al. (6) have demonstrated that the rate of the regulatory volume increase is inhibited by DMA at a concentration of 10 µM but not 1 µM.
The ability of ANG II to stimulate Na+/H+ exchange has been observed previously in vascular smooth muscle and other tissues (3, 7, 21, 26, 29). In a number of tissues, the stimulation of Na+/H+ exchange by ANG II is thought to involve activation of protein kinase C (11). Mechanistically, ANG II has been reported to stimulate Na+/H+ exchange partly as a result of a reduction in the Km for external sodium (7) and also through an increase of Vmax that may be, in part, the result of a rise in the number of Na+/H+ exchanger sites on the plasma membrane (3, 7). Although the observed increase of cytoplasmic sodium concentration suggests that Na+/H+ exchange-mediated proton export is stimulated in ANG II-treated NPE cells, no detectable increase of pHi was observed in cells exposed to ANG II.
We propose that ANG II inhibits H+-ATPase-mediated proton export in parallel with activation of Na+/H+ exchange. It was demonstrated earlier that when H+-ATPase is inhibited by bafilomycin A1, activation of Na+/H+ exchange occurs and pHi remains stable (12). Currently, we do not have sufficient information to determine whether a specific mechanism may exist to activate Na+/H+ exchange when H+-ATPase-mediated proton export is inhibited.
The notion of H+-ATPase inhibition in ANG II-treated cells is supported by the finding that ANG II exposure resulted in a significant reduction of pHi in cells in which Na+/H+ exchange was inhibited by DMA. ANG II and the H+-ATPase inhibition bafilomycin A1 exert a similar influence on pHi, lowering pH in DMA-treated cells but not in the absence of DMA. Bafilomycin A1 is a highly selective inhibitor of V-type ATPase activity (4) and is not known to inhibit Na+-K+-ATPase or calcium ATPase activity. Bafilomycin A1 and ANG II have a similar effect on cytoplasmic sodium, both causing a sodium increase that is prevented by DMA. Importantly, ANG II failed to cause an additional increase of sodium in cells exposed to the H+-ATPase inhibitor bafilomycin A1. Furthermore, ANG II and bafilomycin A1 act similarly to suppress the cytoplasmic alkalinization responses that occur after either depolarization with potassium-rich solution or exposure to a mixture of acetylcholine and epinephrine.
Taken together, the cytoplasmic sodium and pH responses constitute indirect evidence for H+-ATPase inhibition in ANG II-treated cells. More direct evidence in support of this concept comes from the results of ATP hydrolysis measurements made by using cultured NPE cells permeabilized by freeze-thaw; a 10-min episode of pretreatment with ANG II was observed to cause significant reduction of H+-ATPase activity. ANG II-mediated H+-ATPase inhibition has also been proposed in studies of kidney cortical collecting duct segments where ATP hydrolysis was measured (18, 30). However, not all tissues respond in the same way. ANG II stimulates H+-ATPase activity in proximal tubule (32).
The detection of ANG-converting enzyme and prorenin at the basal region of the NPE has led previous investigators to suggest that ANG II might be involved in the regulation of aqueous humor production (27, 28). On the basis of the present study, ANG II as well as bafilomycin A1 has the potential to alter the pHi and concentration of sodium in the NPE, changes that could modify the function of the cotransporters and countertransporters that power fluid secretion. Results from the present study suggest that bafilomycin A1 or ANG II could inhibit H+-ATPase and stimulate sodium movement into the NPE via the Na+/H+ exchanger. Such a response might perhaps contribute to the reported ability of H+-ATPase inhibition to reduce short-circuit current across the ciliary epithelium (34).
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ACKNOWLEDGEMENTS |
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This study was supported by National Eye Institute Grant EY-06915, Research to Prevent Blindness, and the Kentucky Lions Eye Foundation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: N. A. Delamere, Dept. of Ophthalmology and Visual Sciences, School of Medicine, Univ. of Louisville, Louisville, KY 40292 (E-mail: delamere{at}louisville.edu).
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.
April 10, 2002;10.1152/ajpcell.00459.2001
Received 25 September 2001; accepted in final form 2 April 2002.
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