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Department of Physiology, Department of Internal Medicine (1 First Division2 Second Division) and 3 Central Clinical Laboratory, Osaka Medical College, Takatsuki 569-8686, Japan
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(Received 27 September 2003;
accepted after revision 23 March 2004; first published online 1 April 2004)
Corresponding author T. Nakahari: Department of Physiology, Osaka Medical College, Takatsuki, 569-8686, Japan. Email: takan{at}art.osaka-med.ac.jp
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Introduction |
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Hosoi et al. (2002) reported that terbutaline induces a triphasic volume change in AT-II cells: an initial cell shrinkage (initial phase), followed by cell swelling (second phase) and a gradual cell shrinkage (third phase). Agonist-induced cell volume changes were reported in salivary acinar cells (Foskett & Melvin, 1989; Nakahari et al. 1990; Nakahari & Imai, 1998), sweat gland cells (Suzuki et al. 1991), antral mucous cells (Fujiwara et al. 1999) and fetal lung cells (Nakahari & Marunaka, 1996, 1997), and they modulate some cellular functions, such as Na+ channel activity in fetal lung cells (Tohda et al. 1994), exocytosis in antral mucous cells (Fujiwara et al. 1999) and ciliary beat frequency of bronchiolar ciliary cells (Shiima-Kinoshita et al. 2004). The terbutaline-induced volume changes in AT-II cells may also play an important role in alveolar Na+ absorption.
In the triphasic cell volume change, activation of Ca2+-sensitive K+ channels evokes the initial phase, subsequent activation of cAMP-activated Na+ channels evokes the second phase and the gradual activation of cAMP-activated Cl– channels maintains the third phase (Hosoi et al. 2002).
An increase in Cl– conductance alone, however, is unlikely to induce a switch from cell swelling (second phase) to cell shrinkage (third phase). To switch from cell swelling to cell shrinkage, the membrane potential of AT-II cells must shift to the hyperpolarization side of the Cl– equilibrium potential (ECl), because NaCl entry induces cell swelling, and by contrast, KCl release induces cell shrinkage.
In terbutaline-stimulated AT-II cells, two possible processes shift the membrane potential to the hyperpolarization side of ECl: a further activation of K+ channels and an activation of the Na+–K+ pump, which increases [K+]i. In the present study, we examined the effects of K+ channel blockers and ouabain (an inhibitor of the Na+–K+ pump) on the third phase. The study is designed to explore the triggering mechanism for delayed cell shrinkage (third phase).
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Methods |
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The control solution (solution A) contained 121 mM NaCl, 4.5 mM KCl, 1 mM MgCl2, 1.5 mM CaCl2, 25 mM NaHCO3, 5 mM NaHepes, 5 mM HHepes and 5 mM glucose (pH = 7.4 adjusted using 1 N HCl). Solutions A–D used in the present study are summarized in Table 1. The concentrations of Na+, K+ and Cl– were varied by mixing appropriate amounts of solutions A, B, C and D. All the HCO3–-containing solutions were aerated with 95% O2 and 5% CO2. In the HCO3–-free solution aerated with 100% O2, NaHCO3 of the control solution was replaced with NaCl. All the experiments were carried out at 37°C. TEA, terbutaline, ouabain, elastase, heparin, and bovine serum albumin (BSA) were purchased from Wako (Osaka, Japan), and amiloride, benzamil and glybenclamide from Sigma (St Louis, MO, USA). Amiloride, benzamil and glybenclamide were dissolved in dimethyl sulfoxide (DMSO) to obtain stock solutions. All reagents were prepared to their final concentrations immediately before the experiments. The final concentration of DMSO did not exceed 0.1%, and 0.1% DMSO was previously confirmed to have no effect on AT-II cell volume.
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Male rats (Slc:Wistar/ST 150–200 g from SLC Inc., Hamamatsu, Japan) were anaesthetized by an intraperitoneal injection of pentobarbital sodium (60–70 mg kg–1), and then heparinized (1000 units kg–1). All experiments were approved by the Animal Research Committee of Osaka Medical College and the animals were cared for according to the guidelines of this committee. AT-II cells were obtained from the rat lungs, as previously reported (Dobbs et al. 1980; Hosoi et al. 2002). AT-II cell purity, which was confirmed by modified Papanicolau staining and immunohistochemical staining of surfactant protein-D (SP-D), was 
70% and AT-II cells were distinguished from other cells on a video monitor based on their intracellular granules and microvilli, as previously reported (Hosoi et al. 2002).
Cell volume measurement
The experimental set-up and the method of cell volume measurement have previously been described in detail (Nakahari & Imai, 1998; Fujiwara et al. 1999; Hosoi et al. 2002; Shiima-Kinoshita et al. 2004). The method of cell volume estimation, which is based on the assumption that cell volume changes to the same extent in all three dimensions, has already been described in detail (Foskett & Melvin, 1989; Suzuki et al. 1991) and accuracy was confirmed by an impedance method, the 1-H NMR method and weight measurements (Nakahari et al. 1990; Larcombe-McDouall et al. 1994). During experiments, we frequently adjusted the focus of the microscope to observe the cells at their maximum diameter, and measured the area of a single cell from a video monitor. Five areas obtained before stimulation (30 s intervals for 2 min) were averaged, and the average area was used as the control value (A0). The relative volume of an AT-II cell was expressed as V/V0[= (A/A0)1.5], where V is the volume, A is the area and the subscript 0 indicates the control value. The values of V/V0 from four experiments were expressed as means ±S.E.M.
The statistical significance of the difference between mean values was assessed using ANOVA. Differences were considered significant at P < 0.05.
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Results |
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Effects of terbutaline
Terbutaline induced a triphasic volume change in AT-II cells: an initial cell shrinkage (initial phase), followed by cell swelling (second phase) and a gradual cell shrinkage (third phase) (Fig. 1A). Following the third phase, the cell volume reached a plateau, and no oscillations were noted (n= 5) when volume was monitored for 40 min from the start of terbutaline stimulation. Hosoi et al. (2002) reported similar cell volume changes in terbutaline-stimulated AT-II cells.
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AT-II cell volume was measured when [K+]o increased from 4.5 to 150.5 mM. In this experiment, NaCl was replaced with KCl, with other ionic compositions kept constant (Table 1). At 30 mM[K+]o, terbutaline induced the triphasic cell volume change (Fig. 2A). At 75 mM[K+]o, terbutaline did not induce any change in cell volume (Fig. 2B). At 150.5 mM[K+]o, terbutaline increased AT-II cell volume, reaching a plateau within 6 min (Fig. 2C). V/V0 values 4 min after the addition of terbutaline (initial phase) were plotted against [K+]0 (Fig. 2D). Terbutaline decreased the volume of AT-II cells at 4.5 mM[K+]o or 30 mM[K+]o, did not change the volume at 75 mM[K+]o and increased the volume at 100 mM[K+]o or 150.5 mM[K+]o, indicating that the initial phase depends on [K+]i. Thus, the initial cell shrinkage is induced by K+ release via K+ channels activated by terbutaline.
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Based on these observations, we conclude that the initial and third phases are induced by KCl release via K+ and Cl– channels, and that the second phase is induced by NaCl entry via Na+ and Cl– channels.
Effects of ouabain
The effects of the Na+–K+ pump on AT-II cell volume were examined. Ouabain (1 mM) increased AT-II cell volume, which reached a plateau within 4 min. The addition of terbutaline further increased the volume, which reached a new plateau (Fig. 5A). AT-II cells were stimulated with terbutaline and ouabain was then added immediately before the third phase, which increased cell volume instead of a gradual decrease (third phase) (Fig. 5B). The experiments were also performed in the presence of amiloride. Amiloride decreased AT-II cell volume, and the addition of ouabain then increased it slightly. The subsequent addition of terbutaline decreased AT-II cell volume, which reached a plateau within 3 min (Fig. 5C). In ouabain-treated cells, terbutaline did not induce the third phase, although it induced the initial and the second phases.
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The effects of other K+ channel blockers (TEA and Ba2+) were examined. The addition of TEA (2 mM) decreased AT-II cell volume (Fig. 6A), whereas quinidine increased it (Fig. 1B). Subsequent addition of terbutaline increased AT-II cell volume, which then gradually decreased (Fig. 6A). Ba2+ (2 mM) induced similar volume changes (Fig. 6B). Thus, TEA and Ba2+ decreased AT-II cell volume, unlike quinidine, but blocked the initial phase induced by terbutaline, similarly to quinidine. Because TEA and Ba2+ inhibited K+ channels activated by terbutaline (Fig. 6A and B), they are unlikely to induce cell shrinkage in unstimulated AT-II cells. There are two possible causes for this cell shrinkage: TEA or Ba2+ inhibit Na+ entry or activate Na+ extrusion. The effects of TEA on Na+ channels were examined. Amiloride added with TEA decreased AT-II cell volume only slightly (stastistically insignificant). The subsequent addition of terbutaline decreased AT-II cell volume (Fig. 6C). Thus, amiloride (1 µM) with TEA inhibited the terbutaline-induced cell swelling, although it did not decrease the volume of unstimulated AT-II cells (Fig. 6C).
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The effects of TEA on the second phase were also examined. TEA added immediately before the second phase (4 min after the terbutaline stimulation) prevented cell swelling and cell volume remained constant (Fig. 7A). However, amiloride, instead of TEA, added immediately before the second phase further decreased cell volume (Fig. 7B). These findings suggest that TEA does not inhibit Na+ channels.
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Effects of TEA on Na+ extrusion
The effects of TEA on the Na+–K+ pump were examined. Ouabain increased AT-II cell volume, reaching a plateau within 3 min (Fig. 9). Terbutaline further increased the volume, which reached a new plateau within 3 min. Subsequent addition of TEA (9 min after terbutaline stimulation) produced no further change (Fig. 9A).
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Figure 5 shows that an increase in Na+–K+ pump activity may trigger the third phase, and Fig. 9 shows that TEA may increase the activity of the Na+–K+ pump. We examined the effects of TEA on the third phase (Fig. 10). In terbutaline-stimulated AT-II cells, TEA added immediately before the third phase enhanced the third phase, i.e. it increased the extent of cell shrinkage (Fig. 10). A similar enhancement of the third phase was induced by Ba2+ and 2,3-diaminopyridine (data not shown).
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TEA depolarizes membrane potential by inhibiting K+ channels (Yoshida et al. 2003), which may increase the activity of the Na+–K+ pump in AT-II cells. AT-II cells were perfused with a high-K+ test solution ([K+]o= 30 mM), which depolarizes membrane potential. The high-K+ test solution decreased AT-II cell volume, which reached a plateau within 3 min. The extent and time course of cell shrinkage induced by the high-K+ test solution were similar to those induced by TEA. Subsequent addition of terbutaline evoked the triphasic volume change in AT-II cells (Fig. 11A), because 30 mM[K+]o, unlike TEA, does not inhibit K+ channels. In the terbutaline-stimulated AT-II cells, the high-K+ test solution (30 mM[K+]o) added immediately before the second phase did not change AT-II cell volume, which then decreased gradually (Fig. 11B). The high-K+ test solution added immediately before the third phase enhanced the third phase (Fig. 11C). Thus, a high [K+]o (30 mM) enhanced the third phase similarly to TEA (Figs 10 and 11C). A high-K+ solution containing 45 mM K+ induced similar cell volume changes. The effects of TEA were mimicked by a high-K+ solution.
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AT-II cells were treated with valinomycin (50 nM, a potassium ionophore), which hyperpolarizes membrane potential. The addition of valinomycin rapidly decreased cell volume, which reached a plateau within 5 min. Stimulation with terbutaline (10 µM) further decreased cell volume, reaching a plateau within 3 min, and cell volume then decreased gradually (Fig. 12A). In terbutaline-stimulated AT-II cells, valinomycin added immediately before the third phase induced a rapid and large cell shrinkage (Fig. 12B). Thus, valinomycin, which hyperpolarizes membrane potential, induced cell shrinkage in unstimulated AT-II cells and enhanced the third phase in terbutaline-stimualted cells.
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Discussion |
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The triphasic volume change was reported to be induced by the activation of K+ channels, subsequent activation of Na+ channels and gradual activation of Cl– channels (Hosoi et al. 2002). In the present study, the initial phase (initial shrinkage) was inhibited by quinidine, TEA, Ba2+ or glybenclamide, but depended on [K+]o: decreased [K+]o induced cell shrinkage and increased [K+]o induced cell swelling.
The third phase (gradual cell shrinkage) was abolished by quinidine or glybenclamide, and it depended on [Cl–]o, i.e. decreased [Cl–]o increased the extent of cell shrinkage under an equilibrium condition (75 mM[K+]o). Thus, the initial and third phases are induced by KCl release via the activation of K+ and Cl– channels.
Not all inhibitors are as specific as may be assumed, and they may affect other cellular functions. However, in the present study, the results of K+ and Cl– channel inhibition studies were consistent with those of ion replacement studies. This indicates that quinine or glybenclamide do at a minimum inhibit the K+ channels or Cl– channels, although we cannot eliminate the possibility that these blockers have non-specific effects.
The second phase (cell swelling) was inhibited by benzamil or glybenclamide, suggesting that this phase is caused by NaCl influx via the activation of Na+ and Cl– channels. Two Na+-permeable channels, which are amiloride-blockable, were reported in AT-II cells: Na+-selective channels and NSCCs (Tohda et al. 1994; Marunaka, 1996; Matalon & O'Brodovich, 1999; Kemp et al. 2001). The present study demonstrated that the main Na+-permeable channels in AT-II cells are Na+ selective, because perfusion with the KCl solution containing quinine evoked cell shrinkage by Na+ release via Na+ channels. However, many studies have shown that NSCCs play an important role as Na+ entry pathway in AT-II cells (Matalon & O'Brodovich, 1999; Kemp et al. 2001). The NSCCs may be regulated by other mechanisms, such as Ca2+, cGMP and protein kinase C (PKC) (Marunaka, 1996; Matalon & O'Brodovich, 1999; Kemp et al. 2001).
Membrane potential plays a key role in cell shrinkage or cell swelling, i.e. the shift of membrane potential to the hyperpolarization side of ECl induces KCl release (cell shrinkage) and vice versa the shift to the depolarization side induces NaCl entry (cell swelling). To switch from NaCl entry to KCl release in the third phase, membrane potential must shift from the depolarization side of ECl to the hyperpolarization side. However, a gradual activation of Cl– channels alone does not shift the membrane potential to the hyperpolarization side of ECl. Three possible causes exist to induce hyperpolarization: inhibition of Na+ channels, further activation of K+ channels and increase in [K+]i.
The present study, however, has demonstrated that Na+ channels remain active in the third phase, as shown in Fig. 5B. Moreover, TEA experiments demonstrated that the third phase was enhanced despite the inhibition of K+ channels (after addition of TEA). If K+ channels are further activated in the third phase, a K+ channel blocker, TEA, added immediately before the third phase probably decreases the extent of cell shrinkage but is unlikely to enhance cell shrinkage. Thus, further activation of K+ channels does not occur in the third phase. These findings suggest that an increase in [K+]i leads to membrane potential hyperpolarization.
A possible mechanism increasing [K+]i is the Na+–K+ pump, because it takes K+ into the cells linked to the extrusion of Na+. The present study demonstrated that the Na+–K+ pump is necessary to induce the third phase, because ouabain blocked the third phase. An increase in Na+–K+ pump activity, which increases [K+]i, may shift the membrane potential to the hyperpolarization side of ECl. Moreover, the Na+/K+ pump is electrogenic, which may also enhance hyperpolarization. In the present experiments, increasing K+ conductance by adding valinomycin, which hyperpolarizes membrane potential, decreased the volume of AT-II cells and enhanced the third phase. Thus, the hyperpolarization induced by the Na+–K+ pump switches net ion transport from NaCl entry to KCl release in AT-II cells.
TEA, a K+ channel blocker, unexpectedly induced cell shrinkage. The present study demonstrated that TEA inhibits K+ channels and does not inhibit Na+ channels (Figs 4 and 5). Therefore, the most likely cause for TEA-induced cell shrinkage is an increase in Na+ extrusion via the Na+–K+ pump. Because the action of TEA was abolished by ouabain, and TEA enhanced the third phase (which is triggered by the Na+–K+ pump), these results suggest that TEA increases Na+–K+ pump activity.
The effects of TEA were mimicked by a solution with a high [K+]o, such as 30 mM or 45 mM. Increasing [K+]o or the inhibition of K+ channels by TEA induces the depolarization of membrane potential in salivary acinar cells (Yoshida et al. 2003). The depolarization was reported to increase Na+–K+ pump currents in cardiac myocytes (Gadsby et al. 1985) and Xenopus oocytes (Lafaire & Schwarz, 1986) and increase the affinity of the Na+–K+ pump to cytoplasmic Na+ (Rakowski et al. 1997; Barmashenko et al. 1999). These findings suggest that the depolarization of membrane potential may increase Na+/K+ pump activity. An increase in Na+–K+ pump activity results in an increase in [K+]i, which in turn hyperpolarizes membrane potential above ECl.
However, in TEA-treated cells, amiloride did not induce further cell shrinkage. The Na+–K+ pump activity increased by TEA may decrease [Na+]i of AT-II cells to an extremely low level; under these conditions, the inhibition of Na+ entry induces no cell shrinkage. Unfortunately, we do not know the [Na+]i of AT-II cells at present, and further experiments are required.
Moreover, TEA delayed terbutaline-induced cell swelling in ouabain-treated cells. This suggests that Na+ entry via Na+ channels decreases in the presence of TEA because this delayed cell swelling is amiloride-sensitive. These observations suggest that the depolarization of membrane potential also reduces Na+ influx by decreasing the driving force for Na+ entry.
Quinidine induced cell swelling in unstimulated cells, although TEA, 2,3-diaminopyridine and Ba2+ induced cell shrinkage. In terbutaline-stimulated fetal lung cells, the response to Ba2+ is different from that to quinine (Nakahari & Marunaka, 1997). In a perfused rat submandibular gland, acetylcholine-stimulated basolateral K+ release is completely inhibited by quinine and quinidine, but is only partially inhibited by TEA and Ba2+ (50%) (Ishikawa et al. 1994). In patch clamp studies in rat submandibular acinar cells, TEA was reported to inhibit Ca2+-activated maxi-K+ channels in submandibular acinar cells but not quinine-sensitive K+ channels (Ishikawa et al. 1994; Ishikawa & Murakami, 1995). These findings suggest that AT-II cells have two types of K+ channel: one is TEA-, Ba2+- and 2,3-diaminopyridine-sensitive and the other is TEA-insensitive but quinidine-sensitive. Thus, partial inhibition of K+ channels caused shrinkage of AT-II cells, although a complete inhibition of K+ channels induced cell swelling.
In conclusion, terbutaline induces the activation of K+ channels and the subsequent activation of Na+-selective channels, which induces an initial cell shrinkage (initial phase) followed by cell swelling (second phase). By contrast, in the second phase, the activation of Na+ channels increases Na+ entry and induces depolarization. This depolarization enhances Na+–K+ pump activity, which may increase [K+]i by replacing Na+ with K+. This increase in [K+]o finally shifts the membrane potential to the hyperpolarization side of ECl, which triggers the delayed cell shrinkage (third phase).
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). Terbutaline (10 µM) induced a triphasic volume change in AT-II cells. B, effects of quinidine (1 mM). Quinidine induced cell swelling and subsequent stimulation with terbutaline induced further cell swelling. C, effects of glybenclamide (200 µM). Glybenclamide did not induce any changes in cell volume. Paired values marked by arrows and asterisks were significantly different (P < 0.05).
