Department of Cellular and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
Submitted 29 August 2003 ; accepted in final form 1 November 2004
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ABSTRACT |
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stretch-activated cation channels; Ca2+-activated Cl channels; voltage-dependent Ca2+ channels; large-conductance Ca2+-activated K+ channels; gadolinium
Several types of mechanosensitive channels in vascular smooth muscle have been described, including Ca2+-activated K+ channels (KCa), volume-sensitive Cl channels, and nonselective cation channels (9). In most of these studies, mechanosensitive channels were activated by application of negative or positive pressure to the patched membrane or by application of a hyposmotic challenge to induce a volume increase in isolated smooth muscle cells. It is therefore uncertain whether these mechanical stresses mimic mechanical stimuli under physiological conditions. To further elucidate the contribution of mechanosensitive channels to myogenic contraction, it is necessary to characterize the type of channels activated by these mechanical stresses in intact tissues.
In this study, a hyposmotic challenge was applied to both ring segments and isolated cells of canine basilar arteries to determine the types of ion channels contributing to hypotonically induced responses. We demonstrate that the contractile response to a hyposmotic challenge is inhibited by the VDCC blocker nicardipine, the cation channel blockers Gd3+ and ruthenium red, and the Cl channel blockers DIDS and niflumic acid. The ion channels activated by a hyposmotic challenge were further investigated using patch-clamp analysis. We have shown that a hyposmotic challenge indirectly activates Ca2+-activated Cl (ClCa) channels by elevating intracellular Ca2+ concentration ([Ca2+]i). Collectively, our findings suggest that a hyposmotic challenge first activates Gd3+-sensitive cation channels, which in turn activate ClCa channels by elevating [Ca2+]i, and that the activation of both channels results in membrane depolarization, thereby activating VDCC and causing contraction.
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METHODS |
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Tension measurements.
Isometric tension was measured as previously described (24, 25). Briefly, a cylindrical segment of the basilar artery, 20 mm long, was isolated and cut into ring segments 23 mm in width. Endothelial cells were removed from all arteries by rotating a stainless steel rod along the luminal surface; successful removal was confirmed by the absence of acetylcholine (30 nM)-induced relaxation of the artery precontracted with U46619
[GenBank]
(100 nM). The ring segments were mounted on two tungsten wires (0.1 mm diameter), with one attached to a force transducer (T7-8-240; Orientec, Tokyo, Japan) and the other to a micromanipulator, under 0.3-g resting tension in isolated organ baths comprising the isotonic bath solution containing (in mM) 65 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, and 160 mannitol (pH 7.4; 310 mosM), aerated with 100% O2 at 37°C. When the resting tension of 0.3 g was applied, a ring segment was stretched to
150% of the initial wall length, which evoked reproducible maximal contractile responses as previously described (24, 25). Data were stored and analyzed on a computer with the MacLab system (ADInstruments, Castle Hill, Australia). The preparations were allowed to equilibrate for 40 min before each experiment. The osmolarity of the bath solution was reduced by the removal of mannitol without an alteration of the ionic strength, and the isotonic bath solution was replaced with the hypotonic bath solution containing (in mM) 65 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, and 20 mannitol (pH 7.4; 170 mosM).
Current measurements.
Single arterial smooth muscle cells were enzymatically isolated from canine basilar arteries as described previously (16). Briefly, the dissected basilar arteries were cut into small segments and placed in Ca2+-free Hanks' solution containing (in mM) 125 NaCl, 5.4 KCl, 15.5 NaHCO3, 0.44 KH2PO4, 0.34 Na2HPO4, 10 glucose, and 2.9 sucrose, aerated with 95% O2-5% CO2 for 90 min at 37°C. Every 15 min, Ca2+-free Hanks' solution was replaced with fresh solution. The segments were then transferred to the Ca2+-free Hanks' solution containing 1.5 mg/ml collagenase (type IA; Sigma, St. Louis, MO), 0.1 mg/ml protease (type XIV; Sigma), 0.2 mg/ml Mg2+-ATP, 2.0 mg/ml trypsin inhibitor (type I-S; Sigma), and 4.0 mg/ml bovine serum albumin, and incubated for 15 min at 37°C with gentle agitation. After digestion, the supernatant was discarded and the remaining segments were rinsed and further incubated in Kraftbrühe solution containing (in mM) 110 KOH, 70 glutamic acid, 10 taurine, 25 KCl, 10 KH2PO4, 5 HEPES, 0.5 EGTA, and 11 glucose (pH 7.4) for 15 min. Single cells were dispersed by gentle agitation with a wide-pore glass pipette. Isolated cells were kept in Kraftbrühe solution containing 1 mg/ml bovine serum albumin and 0.5 mg/ml trypsin inhibitor at 4°C and were used within 6 h.
The dispersed cells were placed in a small chamber on the stage of an inverted microscope (Diaphot-TMD; Nikon, Tokyo, Japan) and continuously superfused with the isotonic extracellular solution containing (in mM) 70 NaCl, 1 BaCl2, 1 CaCl2, 5 HEPES, and 150 mannitol (pH 7.4; 300 mosM). Micropipettes had a resistance of 25 M when filled with the pipette solution containing (in mM) 130 CsCl, 5 HEPES, 0.1 EGTA, 10 tetraethylammonium (TEA), and 4 Na2-ATP (pH 7.4). Single cells were voltage clamped, and membrane currents were recorded in the whole cell configuration using the patch-clamp technique with a patch-clamp amplifier (Axopatch 200B; Axon Instruments, Foster City, CA). pCLAMP software (version 8.1.0; Axon Instruments) was used to generate command pulses and record data. Current records were low-pass filtered at 1 kHz (3 dB), digitized at 5 kHz by an analog-to-digital converter (DigiData 1200A; Axon Instruments), and stored on a computer (Endeavor Pro-500L; Epson Direct, Japan). Membrane voltages were corrected for the liquid junction potential between the pipette and bath solutions. Leak subtraction was not performed. Experiments were performed at room temperature. The osmolarity of the superfusing solution was reduced by the removal of mannitol without an alteration of the ionic strength.
Drugs. The following drugs were used. Gadolinium chloride, iberiotoxin, nicardipine, N-methyl-D-glucamine (NMDG), and niflumic acid were obtained from Sigma; 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), ryanodine, ruthenium red, and thapsigargin were obtained from Wako (Osaka, Japan); and fura-2 acetoxymethyl ester (fura-2 AM) was purchased from Dojindo Laboratories (Kumamoto, Japan).
DIDS, fura-2 AM, niflumic acid, and thapsigargin were dissolved in dimethyl sulfoxide. We confirmed that the final solvent concentration (0.11.0%) had no effect on contractile responses or membrane currents. Other drugs were dissolved in water.
Statistical analysis. Data are expressed as means ± SE, and n indicates the number of experiments performed. The effects of treatment were analyzed with the paired or unpaired Student's t-test or analysis of variance, followed by Bonferroni's post hoc test. P < 0.05 was accepted as the level of statistical significance.
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RESULTS |
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DISCUSSION |
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Our study confirms earlier observations demonstrating contractions in response to hyposmotic challenge in rat cerebral arteries (6, 20, 33), portal veins (6, 20, 33), and guinea pig aortae (6, 20, 33). In agreement with these studies, we have demonstrated that hypotonically induced contractions of canine basilar arteries were nearly abolished by the VDCC blocker nicardipine. These findings suggest that hypotonically induced contraction is produced by Ca2+ influx through VDCC.
The activation of VDCC could be caused by membrane depolarization. The electrophysiological experiments with a glass microelectrode have demonstrated that hyposmotic challenge causes membrane depolarization sensitive to Gd3+ in rat cerebral arteries (33). In line with this finding, we have shown that hypotonically induced contractions were inhibited by Gd3+. Although Gd3+ does directly inhibit VDCC in other cell types (3, 11, 19), we have confirmed that even at a high concentration of 100 µM, Gd3+ had no inhibitory effects on high-K+-induced contraction in canine basilar arteries. These results suggest that osmotic cell swelling opens Gd3+-sensitive cation channels, thereby causing membrane depolarization and VDCC activation. The data with ruthenium red also support the involvement of cation channels in the response. Our findings are in agreement with earlier observations that cell swelling activates Gd3+-sensitive cation currents in isolated smooth muscle cells of rat mesenteric arterioles (27) and cerebral arteries (33).
Nevertheless, the substitution of NMDG for Na+ in the bath solution did not significantly change the hypotonically induced contraction. This implies that Na+ influx through cation channels is not essential for hypotonically induced membrane depolarization. However, these data do not necessarily rule out the possible contribution of cation channels to hypotonically induced contraction. It is noteworthy that Na+-free extracellular solution augments contraction by inhibiting the Ca2+ extrusion via a Na+/Ca2+ exchanger (4). Possibly, this augmentation may have somewhat counteracted the inhibitory effect of the Na+ substitution on hypotonically induced membrane depolarization. Another possibility is that Ca2+ influx through cation channels primarily contributes to hypotonically induced membrane depolarization.
Nelson et al. (23) showed that the Cl channel blockers IAA-94 and DIDS caused hyperpolarization and dilatation of pressurized rat cerebral arteries, suggesting the contribution of Cl channels to myogenic depolarization in rat cerebral arteries. In contrast, a recent report by investigators at the same laboratory (33) identified a swelling-activated cation conductance that was sensitive to Cl channel blockers such as DIDS and tamoxifen in rat cerebral artery myocytes. In light of these findings, they concluded that a cation channel sensitive to Cl channel blockers is essential for swelling- and pressure-induced depolarization in rat cerebral arteries. In our experiments, the hypotonically induced contraction of canine basilar arteries was inhibited not only by Gd3+ but also by DIDS and niflumic acid. These results might support the presence of a swelling-activated cation channel sensitive to Cl channel blockers. However, our patch-clamp experiments have indicated that the outwardly rectifying currents activated by hyposmotic challenge are Cl currents because the reversal potential for the swelling-activated whole cell currents did not change when [Na+]o was reduced but did shift accordingly when pipette Cl concentrations were reduced. Moreover, the hypotonically induced currents that we recorded were abolished by 10 mM BAPTA in the pipette solution and by the removal of extracellular Ca2+. These results suggest that the swelling-activated, outwardly rectifying currents are ClCa currents that are secondarily activated by an elevation of [Ca2+]i. Furthermore, the hypotonically induced contraction was enhanced by the reduction of the extracellular Cl concentrations, which suggests the contribution of Cl efflux to the contraction. It is thus likely that [Ca2+]i elevation induced by a hyposmotic challenge activates ClCa channels, which in turn cause membrane depolarization (Fig. 8).
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The molecular identity of SAC channels in vascular smooth muscle cells has not been resolved. It has recently been shown, however, that a mammalian transient receptor potential (TRP) homolog of the canonical subfamily (TRPC), TRPC6, a Ca2+-permeable cation channel, is involved in the pressure-induced depolarization of rat cerebral arteries (32). Another TRP homolog cation channel of the vanilloid subfamily (TRPV), TRPV2, also has been shown to be activated by a hyposmotic challenge in mouse aortic myocytes (22). It is possible, therefore, that TRP homologs comprise the arterial SAC channel. The present study also has shown that the hypotonically induced contraction was inhibited by ruthenium red, a specific blocker of TRPV channels, suggesting that the cation channel activated by hypotonicity in canine basilar artery myocytes may be a TRPV homolog. Because we could not detect cation currents activated by hypotonicity in the patch-clamp experiments, the identity of the channels remains to be determined. Although we do not have a clear explanation why the cation currents were not detected, it is possible that the currents may have been too small to be detected under our experimental conditions.
Alternatively, the possibility still remains that Gd3+ might directly inhibit the Cl channels activated by cell swelling. Although Gd3+ does not appear to block swelling-activated Cl channels in vascular smooth muscle cells (35), Gd3+ has been shown to inhibit ClCa channels (28), Ca2+-inactivated Cl channels (2), and hypotonicity-activated Cl channels (1) in Xenopus oocytes. The results of the present study, however, suggest that the Ca2+ influx through cation channels is an obligatory step in the hypotonicity-activated ClCa channels. It is more likely, therefore, that Gd3+ inhibits cation channels, thereby secondarily inhibiting ClCa channels (Fig. 8).
Interestingly, both ClCa channels and BKCa channels can be activated by [Ca2+]i elevation, with the activation of these channels leading to depolarization and hyperpolarization, respectively, in vascular smooth muscles. In canine basilar arteries, a ClCa channel-mediated depolarization seems to be more prominent than a BKCa channel-mediated hyperpolarization in response to hyposmotic challenge. This difference may be attributable to the voltage dependence and Ca2+ sensitivity of BKCa channels; at resting membrane potential, BKCa channels may not be sufficiently activated by increases in [Ca2+]i to activate ClCa channels. It has been shown that BKCa channels are activated by [Ca2+]i elevations, with Kd of 10 µM at 83 mV and 1.8 µM at 11 mV (7), while the Kd for ClCa channels is 0.37 µM (26). Therefore, ClCa channels may first be activated by an increase in [Ca2+]i induced by Ca2+ influx through cation channels, which leads to membrane depolarization and further increases in [Ca2+]i sufficient to activate BKCa channels.
It has been hypothesized that stretch-induced depolarization cannot be maintained unless an endogenous inhibitor of BKCa channels is produced and that 20-hydroxyeicosatetraenoic acid (20-HETE) may be one such substance (13). Our previous studies of the ring strips of canine basilar arteries, in which we found that the contraction induced by mechanical stretch was potentiated by BKCa channel blockers such as iberiotoxin, charybdotoxin, and TEA (25) or 20-HETE (24), support these views. The idea that BKCa channels counteract stretch-induced depolarization is also supported by the present study, which has shown that the selective BKCa channel blocker iberiotoxin drastically increased the hypotonically induced contraction. Because the resting tension was not affected by iberiotoxin, BKCa channels were unlikely to have been activated in the resting state. These results are in agreement with earlier studies showing that iberiotoxin increases the magnitude of longitudinal, stretch-induced, cation channel-mediated membrane depolarization in isolated coronary myocytes (34). Although we have not examined the mechanism for the activation of BKCa channels by a hyposmotic challenge, it is likely that BKCa channels are secondarily activated by an elevation of [Ca2+]i.
It is unclear whether mechanical stimulation of cell swelling and stretch activates the same signal transduction pathways. The present study has demonstrated that the contraction induced by hyposmotic challenge shares several features of the stretch-induced myogenic response. First, hypotonically induced contraction was inhibited by a VDCC blocker. Myogenic tone is also attenuated by VDCC blockers in most smooth muscle preparations (9). Second, hypotonically induced contraction was inhibited by Gd3+. Because the high-K+-induced contraction of canine basilar arteries was not affected by Gd3+ at the concentration we used (100 µM), the inhibition of hypotonically induced contraction is likely to result from the inhibition of Gd3+-sensitive cation channels and not from the direct inhibition of VDCC by Gd3+. Our previous study showed that Gd3+ inhibits myogenic response induced by mechanical stretch in the ring segments of canine basilar arteries (25). Gd3+ also reverses membrane depolarization induced by intraluminal pressure in rat cerebral arteries (33). Moreover, Gd3+-sensitive cation currents are activated by whole cell stretch of isolated vascular smooth muscle cells (8). Thus the activation of Gd3+-sensitive cation channels may be an obligatory pathway in both myogenic response and hypotonically induced contraction. However, the role of Gd3+-sensitive cation channels seems to be somewhat different because the activation of Gd3+-sensitive cation channels is the main cause of depolarization associated with myogenic contraction, whereas it is a trigger event for hypotonically induced contraction.
It is of interest that 100 µM niflumic acid, an effective blocker of ClCa channels, does not affect myogenic tone in pressurized rat cerebral arteries (23). In the present study, the same concentration of niflumic acid nearly abolished hypotonically induced contraction. Because niflumic acid is known to block some types of nonselective cation channels (10, 29) and VDCC (the present study), part of the effect of niflumic acid may be due to a direct inhibition of cation channels and/or VDCC. However, the apparent difference in the sensitivity to niflumic acid suggests that ClCa channels contribute to hypotonically induced contraction, but not to myogenic contraction.
Depletion of the SR Ca2+ store with ryanodine or thapsigargin increases myogenic tone in pressurized skeletal arterioles (30) and cerebral arteries (15). These drugs also abolish Ca2+ sparks, which are highly localized elevations of [Ca2+]i occurring in close proximity to the plasma membrane in pressurized cerebral arteries (15). At physiological potentials, Ca2+ sparks are proposed to stimulate BKCa channels, thereby causing membrane hyperpolarization. In this study, treatment with thapsigargin did not cause significant changes in contraction induced by hyposmotic challenge, suggesting a minimal role for Ca2+ release from the SR in hypotonically induced contraction. However, these results do not necessarily rule out the possible contribution of the Ca2+ release to the contraction. The present study has shown that not only BKCa channels but also ClCa channels are activated during hypotonically induced contraction. Because both channels could be activated by Ca2+ release from the SR, they may effectively oppose each other's effects on contraction.
In this study, a hypotonic solution was prepared by removing mannitol from an isotonic solution containing mannitol. If hyposmotic stimulation was achieved by reducing extracellular NaCl concentration, then the concentration gradients of Na+ and Cl would be decreased, which would lead to a decrease in inward Na+ currents and an increase in inward Cl currents. Therefore, reducing extracellular NaCl concentration was unsuitable for the purposes of the present study. Because Na+ was isosmotically replaced by mannitol, the isotonic solution in our study contained only 65 or 70 mM Na+. Such low [Na+]o is not physiological and may have affected the reactivity. Partial isosmotic replacement of NaCl with mannitol has been shown to lead to a transient depolarization, followed by a partial recovery, in vascular smooth muscle cells (20). Therefore, the amplitude of the hypotonically induced contraction observed in the present study may have been overestimated because of membrane depolarization induced by low [Na+]o. It also has been shown that stretch-induced myogenic tone, but not histamine-induced tone, is increased by reducing [Na+]o with ion substitution in rabbit facial veins and cerebral arteries (14). In this case, the mechanism seems to be independent of membrane depolarization because the enhancement is not inhibited by a Ca2+ channel blocker. This enhancement mechanism is unlikely to be involved in the hypotonically induced contraction in canine basilar arteries, because the contraction was nearly abolished by nicardipine.
In summary, a hyposmotic challenge evoked contraction of canine basilar arteries. The contraction was inhibited by nicardipine (a VDCC blocker), by Gd3+ (a cation channel blocker), and by DIDS and niflumic acid (Cl channel blockers) and was enhanced by reducing extracellular Cl concentration. Our patch-clamp experiments also provide evidence that a hyposmotic challenge activates ClCa channels by elevating [Ca2+]i in canine basilar artery myocytes. On the basis of our present findings, we propose the following mechanism for hypotonically induced contraction (Fig. 8). Osmotic cell swelling first activates Ca2+-permeable, Gd3+-sensitive cation channels, most likely SAC channels, through which Ca2+ influx activates ClCa channels. The Cl efflux through ClCa channels results in membrane depolarization, thereby activating VDCC and causing contraction.
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
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