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(Hypertension. 1998;31:254.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Stretch-Activated Channels in Arterial Smooth Muscle of Genetic Hypertensive Rats

Yusuke Ohya; Natsuko Adachi; Yoshito Nakamura; Motoko Setoguchi; Isao Abe; Masatoshi Fujishima

From the Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

Correspondence to Yusuke Ohya, MD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-ku Fukuoka 812-82, Japan. E-mail ohya{at}intmed2.med.kyushu-u.ac.jp

	Abstract

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Electrical and contractile responses of small arteries to mechanical stress are reportedly enhanced in spontaneously hypertensive rats (SHR), compared with those in Wistar Kyoto rats (WKY). We have previously shown that stretch-activated cation channels exist in arterial smooth muscle membrane, of which opening causes Na⁺ and Ca²⁺ influx and membrane depolarization. We thus hypothesize that activation of stretch-activated channels is enhanced in arterial smooth muscle of SHR compared with WKY. To test this hypothesis, stretch-activated channels is enhanced in arterial smooth muscle cells of resistance mesenteric arteries from SHR and WKY (16 to 24 weeks of age). In the whole-cell recording, membrane stretch was applied by inflating the cell with positive pressure to the recording pipette. Cell-inflation evoked Gd³⁺ -sensitive cation currents. This current appeared with less stretch stimulation and its amplitude was larger in SHR cells compared with WKY cells. In the cell-attached recording, suction to the recording pipette evoked single stretch-activated channel currents (conductance of 32 pS with 150 mmol/L Na⁺), which were blocked by Gd³⁺. Channels were activated with less negative pressure and their availability was greater in SHR cells than in WKY cells. Results suggest that the activation of stretch-activated channels is enhanced in smooth muscle of resistance arteries from SHR compared with WKY, which may contribute to the enhanced vascular responses to mechanical stress in SHR.

Key Words: electrophysiology • vascular smooth muscle • stretch • hypertension • mechanosensitive channel

Abbreviations: SHR = spontaneously hypertensive rats • WKY = Wister Kyoto rats • SA channels = stretch-activated channels • 20-HETE = 20-hydroxyeicosateteraenoic acid

	Introduction

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Mechanical stress to small arteries and arterioles generates active tension.¹ This myogenic response to mechanical stimuli have been reportedly exaggerated in spontaneously hypertensive rats (SHR), when compared with Wistar Kyoto rats (WKY), in various vessels such as the renal vasculature, skeletal muscle arterioles and cerebral arteries.^2–4 It has also been reported that membrane depolarization in response to the increase in luminal pressure is greater in the cerebral artery from SHR than that from WKY.⁵. Since Ca²⁺ channel blockers and removal of extracellular Ca²⁺ correct these exaggerated responses, the alteration would be explained in part by the increased Ca²⁺ influx.^1–3,5 However, mechanism for the enhanced depolarization and increased Ca²⁺ influx in SHR arteries in response to mechanical stress has not been fully clarified. We have previously shown that stretch-activated (SA) nonselective cation channels exist in arterial smooth muscle cells using the whole-cell patch clamp technique.⁶ Opening of these channels causes Ca²⁺ and Na⁺ influx and membrane depolarization, which would contribute to the myogenic contractile response. We thus hypothesize that the activity of SA channels is enhanced in arterial smooth muscle from SHR than from WKY. In the present study, to clarify this possibility, we compared SA channels in smooth muscle cells of small mesenteric arteries from SHR and WKY, using whole-cell and cell-attached configurations of the patch clamp technique. Membrane stretch was applied by positive pressure through the recording pipette to inflate cell in the whole-cell configuration, and by negative pressure through the recording pipette in the cell-attached configuration.

	Methods

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Animals
Experiments were performed on 16- to 24-week-old SHR and WKY, which had been obtained from the Disease Model Cooperative Research Association (Kyoto, Japan). The study protocol was approved by the committee on Ethics of Animal Experimentation in the Faculty of Medicine, Kyushu University. Systolic blood pressure was measured by the tail-cuff method. The systolic blood pressure of SHR (232±6 mm Hg, n=14) was significantly higher than that of WKY (144±4 mm Hg, n=14; P<.01).

Preparation of Single Cells
Rats were anesthetized with ether and then decapitated. The resistance mesenteric arterial branch (diameter <300 µm) was dissected out, and single smooth muscle cells were obtained by collagenase treatment, as previously reported.^6,7 Cells were used for current recording within 4 hours after cell preparation.

Electrical Recording
The whole-cell and cell-attached voltage-clamp techniques were performed with a patch pipette through a voltage-clamp amplifier (Axopatch 1-D, Axon Instruments) by the method of Hamill et al.⁸ The conditions and procedures were basically the same as those previously published.^6,7,9 Recording electrodes were made from Pyrex glass capillary tubing (tip diameter of 1.2 to 1.4 µm; resistance of about 4 M). For the recording of membrane currents and data analysis, pClamp (Axon Instruments) was used on a PC-AT compatible computer. Membrane currents were low-pass-filtered at 1 kHz, digitized with a sampling frequency of 5 to 10 kHz, and stored in a personal computer system for subsequent analysis. Cell capacitance was measured by a cancellation network in the voltage-clamp amplifier. Electrical recordings were performed at room temperature (22° to 24°C).

Solutions and Chemicals
In the whole-cell configuration, the pipette was filled with a high Cs⁺ solution of the following composition (mmol/L): Cs aspartate, 130; CsCl, 20; MgCl₂. 1; EGTA, 10; HEPES, 10; pH 7.3 titrated with CsOH, to block the K⁺ channel currents. The bath solution consisted of a physiological salt solution containing (mmol/L) NaCl, 150; KCl, 6; MgCl₂, 2; glucose, 5.4; HEPES, 5; pH 7.3 titrated with NaOH or TrisOH. Nicardipine (2 µmol/L, a gift from Yamanouchi Pharmaceutical) was added to suppress voltage-dependent Ca²⁺ currents.

For the cell-attached configuration, in order to record single channel currents, the pipette contained high Na⁺ -solution (mmol/L); NaCl, 150; MgCl₂, 0.2; glucose, 5; HEPES, 5; pH 7.3 titrated with NaOH. The bath contained high-K⁺ solution to depolarize the cell membrane to about 0 mV, which consisted of (in mmol/L) KCl, 140; TEACl, 10; MgCl₂, 2; EGTA, 5; glucose, 5; HEPES, 10; pH 7.3 titrated with KOH.

Methods for Applying Membrane Stretch
During the whole-cell recording, a positive pressure was applied to the patch electrode to inflate the cell as has been reported.^6,10 Pressure was controlled by a standing cylinder filled with 10 cm to 30 cm water. With a positive pressure, the cell first formed localized membrane bulla, and then the bulla spread around the cell. The cell then changed its shape from spindle to oval gradually and progressively. The dynamic changes in cell size were recorded under an inverted microscope (Nikon Diaphot-TMD, Nikon) with a Hoffman modulation contrast apparatus (Modulation Optics) and a video monitor system (Teli, Tokyo Electronic). Images were stored in a videotape for subsequent analysis. Cell images were then visualized, and the horizontal cross-sectional areas were measured in a Macintosh computer with NIH Image, an image processing and analysis program (National Institutes of Health, USA). The change in the cross-sectional area was expressed relative to the area before cell inflation, and used as an index of membrane stretch.⁶

The cell inflation often resulted in rupture of the cell membrane of of the patch seal at the end of the experiments, but the resulting artifact currents were easily distinguished from the SA current; the artifact current was amplified abruptly and steeply.

In the cell-attached configuration, in order to stretch the membrane, a negative pressure was applied to the recording pipette by a syringe that was connected with a water-filled manometer. The pressure was turned on and off by a valve connected between the syringe and the recording pipette. A pressure value was used as an index of membrane stretch, since pressure and stretch have a linear relationship above a pressure of 2 cmHg.¹¹ Deterioration of the membrane caused spontaneous opening of channels with large conductances (>60 pS), which was easily distinguished from the SA channels.

Statistical Methods
Data are expressed as means±SEM. Statistical significance was determined by an unpaired t test or one-way ANOVA. P<.05 was considered as statistically significant.

	Results

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In the whole-cell configuration, positive pressure to the recording pipette caused cell inflation. With a holding potential of -50 mV, an inward current appeared after the application of positive pressure (Fig 1A). In this cell, a current appeared when the cross-sectional area increased to more than 1.2 times that of the control. The current disappeared with cell deflation by removal of pressure.

View larger version (21K): [in this window] [in a new window]   Figure 1. Stretch-activated (SA) current recorded with the whole-cell configuration. A, Time dependent changes in the membrane current (upper panel) and cross-sectional area of the cell (lower panel) during cell inflation and deflation. Pressure (20 cmH2O) was applied to the recording pipette (indicated by the bar) to inflate the cell. Membrane potential was -50 mV. The cross-sectional area is expressed as a relative value, where the area before application of pressure is 1.0. Cell capacitance was 19 pF.B, Current-voltage (I-V) relationship of whole-cell SA current. Current was recorded with a ramp voltage from -110 mV to 10 mV during 100 ms. The difference between the currents recorded before (A) and after (B) the cell inflation is the SA current (C). Cell capacitance was 20 pF. C, Effects of Gd3+ (10 µmol/L and 100 µmol/L) on isolated whole-cell SA currents. Cell capacitance was 22pF. The SA currents are shown after the substraction as in B.

A current-voltage (I-V) relationship of this current was obtained with a ramp pulse from -110 to 10 mV (Fig 1B). Cell inflation amplified the current conductance. The difference in currents before and after cell inflation was considered to be a stretch-sensitive component, namely the SA current. The I-V relationship of the SA current was linear at potentials between 10 mV and -60 mV, while a further hyperpolarization slightly increased the conductance. Application of Gd³⁺, a known blocker of SA cation channels to the bath inhibited the SA current; 100 µmol/L Gd³⁺ nearly abolished the SA current (Fig 1C). Since these characteristics were the same as those of whole-cell SA cation currents in canine coronary artery cells, guinea-pig mesenteric artery cells, and guinea-pig bladder cells,^6,12,13 cell inflation with this method could evoke the SA cation current also in rat measenteric artery cells.

We compared whole-cell SA currents in cells from SHR and WKY. Fig 2 shows the relationship between changes in the cross-sectional area of the cell and the amplitude of SA current in SHR and WKY. In both strains, when the crosssectional area increased over a threshold value, the SA current appeared. The threshold value was determined as the area when the evident current appeared (a shift of the holding current exceeded the noise level). The threshold value was significantly smaller in SHR (1.23 ± 0.03 times, n=14) than in WKY (1.31 ± 0.02 times, n=14, P<.05). These results suggest that a smaller stretch stimulation evoked the SA current in SHR than in WKY. In addition, the amplitudes of SA currents was significantly larger in SHR than in WKY (with a 40% increase in the cross-sectional area; SHR, 1.7 ± 0.3 pA/pF, n=14; WKY, 1.0±0.2 pA/pF, n=14; P<.01).

View larger version (31K): [in this window] [in a new window]   Figure 2. Relationship between the amplitude of SA current and the change in cross-sectional area in cells from spontaneously hypertensive rats (SHR, n=14) and Wistar Kyoto rats (WKY, n=14). Relative membrane area was obtained as in Fig 1A, and the corresponding current amplitude was measured at -50 mV. The amplitude was normalized by cell capacitance. Inset, currents recorded before and after application of positive pressure (20 cmH2O, indicated by bar) in SHR cell (21 pF) and WKY cell (20pF). The dotted line indicates zero current level.

In the next experiment, we recorded single SA channel currents. In the cell-attached configuration, suction to the recording pipette caused opening of channels (Fig 4A). The I-V relationship showed that the single-channel conductance was 32 pS (Fig 4B). Effects of Gd³⁺ were examined (Fig 4C). The pipette was first filled from a tip with the solution without Gd³⁺, and then back-filled with the solution contained 100 µmol/L Gd³⁺. This channel disappeared with the presence of Gd³⁺. These characteristics were basically the same as those observed in other smooth muscle tissues,^12,14,15 and also in good accord with the results of whole-cell SA currents in the present study.

View larger version (18K): [in this window] [in a new window]   Figure 4. Single SA channels in WKY cells and SHR cells. A, Current traces with pressures of -10, -20, and -30 cmH2O. Holding potential was -50 mV. B, Activities of SA channels during application of negative pressure in WKY cells (n = 6) and SHR cells (n = 6). Holding potential was -50 mV. Availability (NPo) is used as an index of the channel activity, where N is the number of channels available for opening in patch membrane and Po is the open probability of each channel. NPo was obtained from the following equation; NPo = (sum of duration of channel opening)/(total recording time).

View larger version (22K): [in this window] [in a new window]   Figure 3. Single SA channel current recorded with the cell-attached configuration. A, Application of negative pressure (suction, -20 cmH2O) to the recording pipette evoked single SA channel currents. Membrane potential was -50 mV. B, The I-V relationship of single SA channel currents. Left panel shows current traces obtained at -10 mV, -40 mV, and -60 mV. Right panel shows the I-V relationship obtained from 5 cells. Slope conductance was 32 pS by linear regression. Current was recorder with a pressure of -20 cmH2O. C, Effect of Gd3+ on single SA channel currents. The pipette was first filled from a tip with the solution without Gd3+. The upper trace (0 min) solution contained 100 µmol/L Gd3+. The upper trace (0 min) was recorded immediately after a giga-ohm seal was obtained. The lower trace was recorded 5 minutes after the giga-ohm seal when Gd3+ was assumed to have reached the patch membrane. Current was recorded with a pressure of -20 cmH2O.

When we compared SHR and WKY, the opening of more than one channel was observed in 83% (10/12). In SHR, negative SHR and in 67% patches in WKY (8/12). In SHR, negative pressures of -10 cmH₂O and more increased the channel opening, while a higher negative pressure (-20 cmH₂O and more) was required in WKY (Fig 4A). A relationship was obtained between the negative pressure applied to the suction pipette and the channel activity (Fig 4B). For an index of the channel activity, we used the availability of channels (NPo; a product of N and Po, where N is the number of channels available for opening in patch membrane and Po is the open probability of each channel). NPo was significantly greater in SHR than in WKY (P<.01 by ANOVA). This graph clearly shows that SA channels were activated with less stretch stimulation and their availability was greater in cells from SHR than in those from WKY.

	Discussion

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In the present study, we recorded whole-cell and single-channel currents of SA channels in arterial smooth muscle cells from SHR and WKY. The threshold stimulation for activation of SA channels was lower in SHR than in WKY; whole-cell SA current appeared with less cell inflation, and single SA channel currents appeared with less negative pressure. In addition, the amplitude of whole-cell SA currents and the availability of single SA channels were greater in SHR than in WKY. Since opening of the SA channel depolarizes the membrane and increases the Ca²⁺ influx,^6,12 the present observation supports the hypothesis that the enhanced activation of SA channels would contribute to the exaggerated electrical and contractile responses to mechanical stress in small arteries of SHR, compared with WKY.

In the present study, membrane stretch was applied by cell inflation with the whole-cell configuration, and a change in the cross-sectional area was used as an index of membrane stretch. We and others have reported that whole-cell SA currents could be evoked with this method.^6,10 The procedure of this method is simple, but it has some limitations. First, the quantification of surface membrane area of the cell may involve error; the cell shape changes from a spindle to oval shape with positive pressure, while we assumed that the surface membrane area simply correlates with its cross-sectional area regardless of their shapes. Second, inflation of the cell may damage the intracellular regulatory component for the activation of SA channels, although its basic component is preserved during cell inflation.⁶. With the use of cell-attached configuration, the stretch was applied by suction to the recording pipette. This method has been widely used for the study of various mechanosensitive channels, although it was once suggested that single channel recording of SA channels with this method might involve artifacts.¹⁶ Since we obtained comparable results in the experiments using the whole-cell and cell-attached configurations, these methodological limitations may not disturb our conclusion that the activation of SA channels is enhanced in SHR cells than in WKY cells.

The basic characteristics of SA channels in small mesenteric arteries from SHR and WKY were nearly the same as those observed in the guinea-pig bladder, stomach and mesenteric artery as well as porcine coronary artery.^6,12–15 For example, these channels were all blocked by 10 to 100 µmol/L Gd³⁺. Channel opening was nearly voltage-insensitive at physiological potentials but showed a slight inward rectification at more hyperpolarized potentials (<-70 mV). In addition, conductance of single SA channels with 150 mmol/L Na⁺ was 32 pS in the present study, 33 pS in guinea-pig bladder cells, 42 pS in guinea-pig gastric cells, and 23 pS in porcine coronary artery cells.

The underlying mechanism for the altered activation of SA channels in SHR arteries has not been clarified in the present study, however several possible mechanisms could be suggested. First, an increased expression of the channel proteins would explain the increased opening (greater availability) of the SA channels. Second, an expressed phenotype of channel protein or its regulatory protein for SA channels¹⁷ may differ between the two rat strains. Third, since differences in lipid characteristics of vascular smooth muscle cells have been noted between SHR and WKY,^18,19 this altered membrane lipid characteristics may contribute to the enhanced activation of SA channels in SHR. For example, turnover of phosphatidylethanolamine was lower and that of phosphatidylserine was greater in vascular smooth muscle cells from stroke-prone SHR compared with those from WKY, although phospholipid composition did not differ between the two strains.¹⁹ It is also known that vascular membrane of SHR has lower fluidity (greater microviscosity) than that of WKY.^18,19 Since physicochemical properties such as membrane fluidity are affected by the content and physiological states of cholesterol, phospholipids, and their fatty acids,²⁰ the differences in lipid characteristics would correspond to the lower membrane fluidity in SHR. Thus, the altered lipid characteristics and membrane fluidity may affect the activation of SA channels. In addition, the increased activities of phospholipase A₂ and cytochrome P = 450 in renal membranes have been reported in SHR compared with WKY,^21,22 where activities of these enzymes could be also affected by membrane lipid characteristics.^19,20 Recent studies have shown that fatty acid²³ or 20-hydroxyeicosatetraenoic acid²⁴ (20-HETE, a cytochrome P-450 metabolite of arachidonic acid) modifies the stretch-activation of K⁺ channels in smooth muscle membrane. Thus, it is also possible that the altered production of fatty acid or 20-HETE may contribute to the alteration of SA channels in SHR. The third possibility is that neural or humoral factors in SHR may alter the SA channels. Since neural and hormonal control of SA channel activity has not been clarified, further information should be accumulated.

Electrical and mechanical responses on mechanical stress have been reportedly exaggerated in arteries from SHR than from WKY.^2–5 From the findings in the present study, we suggest that the enhanced activation of SA channels would contribute to the exaggerated vascular responses to mechanical stress. However, other mechanisms may also contribute to the alteration. For example, since L-type Ca²⁺ currents are larger in vascular smooth muscle cells from SHR than from WKY,^7,25,26 the vascular responses to mechanical stimuli would be greater in SHR than in WKY even with a similar degree of stretch-induced depolarization. In addition, other stretch-dependent mechanisms such as various enzymes²⁷ including phospholipase A and phospholipase C, voltage-dependent Ca²⁺ channels,²⁸ and Ca²⁺ -dependent K⁺ channels²⁹ may also be candidates.¹

A recent study have shown that the activation of mechanosensitive channels in endothelium is enhanced in SHR compared with those in WKY.³⁰ Altered mechanosensitive channels in endothelial cells may contribute to the altered endothelial function in hypertension. Since similar changes occur in parallel in smooth muscle cells and endothelial cells in hypertensive rats, a common mechanism may alter these channels in hypertension.

In conclusion, we have shown that activation of SA channels is enhanced in smooth muscle cells of small mesenteric arteries from SHR than from WKY. The altered SA channels in arterial smooth muscle cells may contribute to the enhanced myogenic responses as well as the generation of hypertrophy and remodeling of arterial tissues in hypertension.

Received September 16, 1997; first decision October 22, 1997; accepted October 31, 1997.

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