Department of Pharmacology, University of Vermont, Burlington, Vermont 05405
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ABSTRACT |
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Ca2+ sparks have been
previously described in isolated smooth muscle cells. Here we present
the first measurements of local Ca2+ transients
("Ca2+ sparks") in an intact
smooth muscle preparation. Ca2+
sparks appear to result from the opening of ryanodine-sensitive Ca2+ release (RyR) channels in the
sarcoplasmic reticulum (SR). Intracellular Ca2+ concentration
([Ca2+]i)
was measured in intact cerebral arteries (40-150 µm in diameter) from rats, using the fluorescent
Ca2+ indicator fluo 3 and a laser
scanning confocal microscope. Membrane potential depolarization by
elevation of external K+ from 6 to
30 mM increased Ca2+ spark
frequency (4.3-fold) and amplitude (~2-fold) as well as global
arterial wall
[Ca2+]i
(~1.7-fold). The half time of decay (~50 ms) was not affected by
membrane potential depolarization. Ryanodine (10 µM), which inhibits
RyR channels and Ca2+ sparks in
isolated cells, and thapsigargin (100 nM), which indirectly inhibits
RyR channels by blocking the SR
Ca2+-ATPase, completely inhibited
Ca2+ sparks in intact cerebral
arteries. Diltiazem, an inhibitor of voltage-dependent
Ca2+ channels, lowered global
[Ca2+]i
and Ca2+ spark frequency and
amplitude in intact cerebral arteries in a concentration-dependent
manner. The frequency of Ca2+
sparks (<1
s1 · cell
1),
even under conditions of steady depolarization, was too low to
contribute significant amounts of
Ca2+ to global
Ca2+ in intact arteries. These
results provide direct evidence that Ca2+ sparks exist in quiescent
smooth muscle cells in intact arteries and that changes of membrane
potential that would simulate physiological changes modulate both
Ca2+ spark frequency and amplitude
in arterial smooth muscle.
ryanodine receptor; membrane potential; calcium channels
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INTRODUCTION |
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LOCAL CALCIUM RELEASE EVENTS through ryanodine-sensitive Ca2+ release (RyR) channels ("Ca2+ sparks") in the sarcoplasmic reticulum (SR) have been described in single smooth muscle cells enzymatically isolated from arteries (6, 26, 28), veins (1), and airway (32). Ca2+ sparks activate nearby Ca2+-sensitive K+ (KCa) channels in isolated smooth muscle cells to cause a transient outward current (26), which has previously been referred to as a "spontaneous transient outward current" (STOC) (2). STOCs cause substantial membrane potential hyperpolarizations (20 mV) in isolated smooth muscle cells (e.g., Ref. 11). It has been proposed that STOCs cause a tonic hyperpolarizing influence on the membrane potential of small pressurized arteries with myogenic tone (26), since inhibitors of Ca2+ sparks (e.g., ryanodine or thapsigargin) or of KCa channels (e.g., iberiotoxin) cause membrane potential depolarization of pressurized cerebral arteries (7, 20, 22, 26).
Intravascular pressure (e.g., from 10 to 60 mmHg) causes a graded
membrane potential depolarization (from 60 to
40 mV), increases arterial wall intracellular
Ca2+ concentration
([Ca2+]i;
from 100 to 200 nM), and maintains constriction of small cerebral arteries (7, 20-22, 26). Inhibitors of
Ca2+ sparks (e.g., ryanodine) or
of KCa channels (e.g.,
iberiotoxin) depolarize, elevate arterial wall
[Ca2+]i,
and cause a tonic constriction of pressurized cerebral arteries (7, 22,
26). Ryanodine and iberiotoxin each block the effect of the other,
suggesting that ryanodine receptors act through KCa channels to affect arterial
membrane potential, arterial wall [Ca2+]i,
and diameter (22, 26, 28). Therefore, based on isolated cell and intact
artery data, it was proposed that pressure-induced membrane potential
depolarization leads to an increase in the steady open probability of
dihydropyridine-sensitive, voltage-dependent ("L-type")
Ca2+ channels that elevates steady
Ca2+ influx (26, 27, 30). The
elevation of Ca2+ influx and
arterial wall
[Ca2+]i
would lead to increased Ca2+ spark
frequency and thereby STOC frequency, which would oppose the
pressure-induced depolarization. Therefore, the
Ca2+ spark
KCa channel pathway would be a
tonic negative feedback element to regulate the membrane potential and
thereby the tone of small cerebral arteries. However,
Ca2+ sparks have not been
identified in intact arteries, and their Ca2+ contribution to global
arterial wall Ca2+ has not been
directly determined in any intact smooth muscle preparation.
The frequency of STOCs in smooth muscle has been shown to increase with membrane depolarization (e.g., Refs. 2, 34). Therefore, RyR channels, and thus Ca2+ sparks, should be modulated by membrane potential through changes in the activity of voltage-dependent Ca2+ channels. Indeed, it is well established that RyR channels in muscle are activated by increases in cytoplasmic and SR Ca2+ (9, 16, 23, 24, 33, 35). Ca2+ influx evoked by depolarizing voltage steps can elicit ryanodine-sensitive changes in global [Ca2+]i in isolated smooth muscle cells, consistent with the idea that RyR channels in smooth muscle can be activated by cytoplasmic Ca2+ (e.g., Refs. 12, 13). However, the voltage dependence of Ca2+ sparks has not been determined in any smooth muscle preparation, including isolated cells.
In this study, we provide the first measurements of Ca2+ sparks in an intact smooth muscle preparation and provide the first information on the voltage dependence of Ca2+ spark frequency and amplitude in smooth muscle. Ca2+ sparks were detected in quiescent arteries, and their frequency and amplitude increased with depolarization to a membrane potential appropriate for pressurized arteries, supporting the role of such events in the negative feedback regulation of arterial diameter. This frequency and amplitude modulation of Ca2+ sparks (cf. Refs. 3, 4) by voltage depends on activation of L-type Ca2+ channels. These results indicate that Ca2+ sparks are not substantially altered by cell isolation and that their properties are modulated by voltage. This argues against the notion that Ca2+ sparks and STOCs result from single cell isolation and Ca2+ overload. The frequency and voltage dependence of Ca2+ sparks in intact arteries are consistent with Ca2+ sparks modulating smooth muscle membrane potential to regulate arterial diameter (cf. Refs. 22, 26).
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METHODS |
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Tissue preparation. Sprague-Dawley rats (12-14 wk) of either sex were euthanized by peritoneal injection of pentobarbital solution (150 mg/kg). The brain was removed and placed into ice-cold, oxygenated (95% O2-5% CO2) physiological salt solution (PSS) containing (in mM) 119 NaCl, 4.7 KCl, 24 NaHCO3, 1.2 KH2PO4, 1.6 CaCl2, 1.2 MgSO4, 0.023 EDTA, and 11 glucose (pH 7.4). In all subsequent procedures, arteries were maintained in ice-cold PSS. Secondary branch posterior cerebral arteries (100-150 µm in diameter, 1-2 mm in length) were removed and cleaned of basolateral connective tissue. Arteries were carefully slipped over rectangular glass cannulas (220 µm × 40 µm × 10 mm) whose ends had been fire polished to reduce luminal arterial damage in a manner similar to that described for studies of Ca2+ oscillations in smooth muscle cells in intact tail arteries of rat (18). The measurements of Iino and colleagues (18) would not have detected Ca2+ sparks, since their image sampling rate (1 image/s) was too slow.
Ca2+ measurements. Arteries on glass cannulas were placed into a physiological K+ solution [6 mM extracellular K+ (K+o); for composition see below] containing 10 µM fluo 3-AM (Molecular Probes) and 0.05% pluronic acid (Molecular Probes) and incubated at 22°C for 60 min. After a 30-min wash at 22°C, arteries were kept on ice until required.
Arteries were imaged using a Noran Oz laser scanning confocal microscope and a ×60 water immersion lens (numerical aperture 1.2) by illumination with a krypton-argon laser at 488 nm. Images of the vessel wall (56.3 × 52.8 µm or 256 × 240 pixels) were recorded every 16.7 ms (60 images/s). For each experiment, Ca2+ spark activity was determined on the same artery before and after the application of elevated external K+ or a drug. To minimize photobleaching and cellular damage due to laser illumination, a given volume of an artery was usually scanned for only 10 s. Areas of each artery were scanned for ~20 s under control conditions, and different areas of the same artery were scanned for a total time of ~20 s in the presence of the test substance. Files were stored on writable compact disk for future analysis. To permit comparison with the single-cell data, all measurements were taken at 22°C.Solutions. Physiological K+ solution (6 mM K+o) contained (in mM) 136 NaCl, 6 KCl, 10 HEPES, 2 CaCl2, 1 MgCl2, and 10 glucose (adjusted to pH 7.4 with NaOH). A high-K+ solution (30 mM K+o; used in this study to depolarize arteries) contained (in mM) 112 NaCl, 30 KCl, 10 HEPES, 2 CaCl2, 1 MgCl2, and 10 glucose (adjusted to pH 7.4 with NaOH). Diltiazem, thapsigargin, and wortmannin were purchased from Sigma, and ryanodine was from Calbiochem.
Analysis. Ca2+ sparks were analyzed using custom software written by Dr. Adrian Bonev in our laboratory (using IDL 5.0.2, Research Systems, Boulder, CO). To determine Ca2+ spark frequency, the frequency (Hz) of Ca2+ sparks in each artery was calculated and these means were averaged, resulting in the mean artery Ca2+ spark frequency for a given condition. Baseline fluorescence (Fo) was determined by averaging six images without activity. Local fractional fluorescence increases (F/Fo) were determined by dividing the fluorescence of an area 1.54 × 1.54 µm (7 × 7 pixels; i.e., 2.37 µm2) in each image (F) by the baseline average Fo. Ca2+ sparks were defined as local F/Fo >1.3. Such increases in fluorescence were not observed in the presence of thapsigargin or ryanodine, supporting the idea that Ca2+ sparks derive from the SR.
Estimates of Ca2+ spark and global arterial [Ca2+]i were made using the equation (8, 10)
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(1) |
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RESULTS |
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Voltage dependence of Ca2+ sparks in intact arteries. Local [Ca2+]i transients (Ca2+ sparks) were observed in smooth muscle cells bathed in physiological K+ solution (6 mM K+o) and in a depolarizing solution of 30 mM K+o (Figs. 1 and 2). This elevation of external K+ increased global [Ca2+]i (fractional fluorescence increase 1.47 ± 0.12) and increased Ca2+ spark frequency 4.3-fold, from 0.24 ± 0.15 to 1.04 ± 0.28 Hz (n = 5 paired arteries; Figs. 2 and 3A). An elevation in global [Ca2+]i through membrane depolarization also causes muscle contraction (e.g., Ref. 21). Movement of the myocytes was minimized by the glass cannula. To reduce further any possible effects of muscle movement, the effects of membrane depolarization by raising external K+ from 6 to 30 mM were tested on five arteries bathed in the contractile inhibitor, 1 µM wortmannin (29). In five paired arteries bathed in 1 µM wortmannin, the frequency of Ca2+ sparks was 0.21 ± 0.11 Hz in 6 mM K+o and increased 5.5-fold to 1.15 ± 0.26 Hz with 30 mM K+o. The half time of decay (t1/2) of the Ca2+ sparks was unchanged by membrane potential depolarization (6 mM K+o, 60.7 ± 10.5 ms, n = 8 sparks; 30 mM K+o, 49.3 ± 8.3 ms, n = 41 sparks). These results indicate that local [Ca2+]i transients (Ca2+ sparks) can be measured in intact cerebral arteries and that their frequency increases with membrane depolarization.
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Ca2+ sparks in intact arteries are abolished by ryanodine and thapsigargin. Ca2+ sparks and STOCs in isolated cerebral artery myocytes are inhibited by ryanodine (10 µM), a blocker of the RyR channel in the SR, and by thapsigargin (100 nM), an inhibitor of the SR Ca2+ ATPase (26). Ryanodine (10 µM) and thapsigargin (100 nM) also abolished Ca2+ sparks in intact cerebral arteries. Ca2+ sparks were not observed in arteries depolarized with 30 mM K+o in the presence of ryanodine (n = 6 arteries) or thapsigargin (n = 6 arteries) (30 min exposure in 6 mM K+o). In the same arteries (in 30 mM K+o) before exposure to ryanodine or thapsigargin, Ca2+ spark frequency was 0.8 ± 0.20 or 1.14 ± 0.25 Hz, respectively.
Ryanodine and thapsigargin caused a fractional fluorescence increase of 1.23 ± 0.11 (n = 6 arteries) and 1.21 ± 0.08 (n = 6 arteries), corresponding to an elevation of global Ca2+ to 280 and 274 nM, respectively. This increase (70 nM) in global Ca2+ after application of ryanodine or thapsigargin is similar to the change in global Ca2+ (50 nM) observed with these agents on pressurized cerebral arteries, measured with fura 2 (22). The increase in global Ca2+ to ryanodine and thapsigargin appears to occur through inhibition of Ca2+ sparks, leading to membrane depolarization and subsequent Ca2+ influx through L-type voltage-gated Ca2+ channels (22, 26).Activation of Ca2+ sparks by depolarization is reversed by Ca2+ channel blockers. Membrane potential depolarization could increase the frequency of Ca2+ sparks through activation of voltage-dependent Ca2+ channels (cf. Refs. 9, 23). This possibility was explored by examining the effects of the L-type Ca2+ channel antagonist, diltiazem, on Ca2+ sparks (diltiazem was used because it is not as light sensitive as the dihydropyridines). Ca2+ sparks were stimulated by depolarization in 30 mM K+o, and control images were acquired, after which 30 or 60 µM diltiazem was applied, and measurements were taken 3-4 min later. Diltiazem (30 µM) reduced the frequency of Ca2+ sparks in five paired arteries from 0.98 ± 0.11 to 0.38 ± 0.12 Hz, or 2.6-fold (Fig. 3B, Table 1). Diltiazem also reduced global arterial wall [Ca2+]i (F/Fo, 0.81 ± 0.05, n = 5 arteries), which corresponds to an estimated change in global [Ca2+]i from 203 to 149 nM (Table 1). Diltiazem reduced the amplitude of Ca2+ sparks (Table 1), based on a reduction in global [Ca2+]i (30 mM K+o control, 1.55 ± 0.02, n = 70 sparks; 30 µM diltiazem, 1.65 ± 0.06, n = 29 sparks). Diltiazem (30 µM) did not alter the t1/2 for Ca2+ sparks (57.6 ± 11.9 ms, n = 6 sparks).
When applied at a higher concentration, diltiazem (60 µM) reduced Ca2+ spark frequency 6.6-fold [control (30 mM K+o), 1.19 ± 0.26 Hz; 60 µM diltiazem, 0.18 ± 0.07 Hz; 7 paired arteries; Fig. 3B], and reduced global arterial wall [Ca2+]i (F/Fo, 0.48 ± 0.01) from 203 to 77 nM (Table 1). The mean peak amplitude of local [Ca2+]i during a Ca2+ spark was also reduced by 60 µM diltiazem from 480 nM in control (30 mM K+o; F/Fo 1.62 ± 0.02, n = 157 sparks) to 173 nM in 60 µM diltiazem (F/Fo 1.87 ± 0.07, n = 25 sparks) (Table 1). Therefore, the change in local [Ca2+]i due to a Ca2+ spark was reduced from 277 nM in 30 mM K+o to 96 nM by 60 µM diltiazem. The t1/2 for Ca2+ sparks that occurred in the presence of 60 µM diltiazem was unchanged (64.3 ± 17.1 ms, n = 12 sparks). These results suggest that activation of voltage-dependent Ca2+ channels is involved in the increase in Ca2+ spark frequency and amplitude caused by membrane potential depolarization.Ca2+ sparks in cerebral arterioles. To determine whether Ca2+ sparks occurred in smaller diameter arteries, a 40- to 50-µm side branch (~250 µm in length) attached to a secondary branch posterior cerebral artery was oriented under the main vessel so that the whole length of the branch could be imaged. Ca2+ sparks were also resolved in this smaller diameter arteriole (Fig. 4). With 30 mM K+o, diltiazem (30 µM) reduced Ca2+ spark frequency from 2.03 ± 0.54 to 0.43 ± 0.17 Hz. The mean peak F/Fo of the Ca2+ sparks was relatively unchanged, with F/Fo of 1.74 ± 0.04 in control (n = 81 sparks) and 1.70 ± 0.06 in the presence of 30 µM diltiazem (n = 17 sparks). These results suggest that Ca2+ sparks also exist in cerebral arterioles.
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DISCUSSION |
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This study presents the first recordings of Ca2+ sparks from an intact smooth muscle preparation, namely resistance-sized (40-150 µm in diameter) cerebral arteries. Ca2+ sparks appeared to be caused by the opening of RyR channels in the SR, based on inhibition by ryanodine and thapsigargin and on their subcellular localization (10, 26). Membrane potential depolarization of intact arteries with elevated K+ (30 mM) increased Ca2+ spark frequency and amplitude, and this effect was reduced in a concentration-dependent manner by the Ca2+ channel inhibitor diltiazem. These results indicate that Ca2+ sparks are regulated by Ca2+ entry through voltage-dependent Ca2+ channels, as has been observed in cardiac muscle (9, 23).
Ca2+ sparks
in intact arteries and isolated cells.
A major advance of the technique described in this study is the ability
to examine local
[Ca2+]i
signals with millisecond time resolution in intact arteries. Enzymatic
separation of single smooth muscle cells from intact tissue leads to
loss of intercellular communication, as well as possible cellular
damage. Our approach permits the simultaneous measurement of
Ca2+ sparks in a number (~8) of
smooth muscle cells and thereby increases the amount of data that can
be collected during scanning. Ca2+
spark properties (frequency, F/Fo,
t1/2) appear to
be similar in the intact arteries and in cells enzymatically isolated
from the same arteries (6, 26, 28).
Ca2+ spark frequency in intact
arteries ranged, depending on voltage, from ~0.2 to 1.2 Hz in a
volume that corresponds to about two to four cells, or 0.05-0.6
Hz/cell. Ca2+ spark frequency was
~1 Hz in isolated cerebral artery myocytes (6, 28) when the scanned
volume was taken into account. STOC frequency in cerebral artery
myocytes was also ~1 Hz when the cells were voltage clamped at
40 mV, a voltage similar to the membrane potential of isolated
myocytes and smooth muscle cells in pressurized (60 mmHg) arteries (6,
7, 21, 26, 28). Therefore, Ca2+
spark frequency in intact arteries depolarized to about
40 mV (30 mM K+o) was in the range of that
measured in isolated myocytes at similar voltages (~0.2-1.0
Hz/cell), particularly in light of uncertainties of precise voltages,
[Ca2+]i,
and scan volumes. Fractional fluorescence changes during a Ca2+ spark and
t1/2 were similar
in intact arteries and isolated myocytes
(F/Fo 1.5-1.9,
t1/2 ~50 ms)
(6, 28).
Membrane depolarization increases
Ca2+ spark
frequency and amplitude in intact arteries.
In the present study, the effects on membrane potential of elevating
pressure to ~60 mmHg were simulated by depolarizing with 30 mM
K+. Elevation of external
K+ from 6 to 30 mM depolarizes
smooth muscle cells in arteries from approximately 60 mV to
40 mV (Refs. 5, 14; for review see Ref. 17), similar to the
depolarizing effect of increasing intravascular pressure to
~60-80 mmHg (7, 15, 20, 21, 26). Based on the fractional
fluorescence change and an arterial wall
[Ca2+]i
of 119 nM in 6 mM K+ (21), this
increase in external K+ raised
global arterial
[Ca2+]i
to 203 nM, a value similar to what was measured (190 nM) with fura 2 in
the same arteries subjected to 60 mmHg (21). Elevated K+ also increased
Ca2+ spark frequency (4.3-fold)
and amplitude (from an estimated peak [Ca2+]i
of 229-460 nM). This membrane potential depolarization-induced increase in Ca2+ spark frequency
and amplitude, as well as the increase in global [Ca2+]i,
should have a profound effect on the activity of
KCa channels, which are presumably
responsible for the observed iberiotoxin- and ryanodine-sensitive
change in membrane potential measured in intact pressurized arteries.
These results are consistent with the idea that
Ca2+ sparks and
KCa channels form a negative
feedback element to limit tonic membrane depolarization and
constriction of cerebral arteries (cf. Ref. 26).
Direct contribution of
Ca2+ sparks to
global
[Ca2+]i
in intact cerebral arteries.
Myogenic cerebral arteries subjected to physiological levels of
intravascular pressure (e.g., 60 mmHg) have steady membrane potentials
of about 40 mV, arterial wall
[Ca2+]i
of ~200 nM, and are constricted by ~30% (7, 20, 21, 25, 26). Under
conditions designed to simulate the effects of pressure on membrane
potential and arterial wall
[Ca2+]i
(i.e., 30 mM K+o),
Ca2+ spark frequency was ~1
s
1 in a volume that
approximately corresponds to two to four cells. One
Ca2+ spark would raise global
[Ca2+]i
in a single cell by <2 nM (see Ref. 26).
Ca2+ release through RyR channels
can contribute significantly to global
[Ca2+]i
in cerebral and coronary artery myocytes, if it is evoked by nonphysiological depolarizing voltage steps with elevated levels of
external Ca2+ (>2 mM) (13, 19)
or by bolus addition of caffeine (13, 19, 22). Nonetheless, under the
conditions used in our experiments (i.e., at room temperature), direct
Ca2+ spark measurements under
steady-state conditions appropriate for pressurized myogenic cerebral
arteries indicate that RyR channels do not contribute sufficient
Ca2+ spatially and temporally to
directly alter global
[Ca2+]i.
Furthermore, in the presence of a
KCa channel blocker (iberiotoxin), ryanodine was without effect on arterial diameter and wall
[Ca2+]i,
also arguing against a significant direct contribution of RyR channels
to steady-state global
[Ca2+]i
(22). However, it is conceivable that under other conditions (e.g., in
the presence of vasoconstrictors)
Ca2+ sparks, perhaps in the form
of Ca2+ waves, could contribute
significantly to global Ca2+
changes in intact arteries (1).
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ACKNOWLEDGEMENTS |
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We thank Dr. Adrian Bonev, Dr. Joseph Brayden, and Dr. George Wellman for comments on the manuscript.
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FOOTNOTES |
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This study was funded by National Heart, Lung, and Blood Institute Grants HL-44455 and HL-51728 and National Science Foundation Grants IBN-9631416 and BIR-9601682 and by a fellowship (J. H. Jaggar) from the American Heart Association, New Hampshire and Vermont Affiliate.
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. §1734 solely to indicate this fact.
Address for reprint requests: M. T. Nelson, Dept. of Pharmacology, The University of Vermont, Burlington, VT 05405.
Received 20 February 1998; accepted in final form 19 March 1998.
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