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Department of Obstetrics and Gynecology, The University of Vermont, College of Medicine, Burlington, Vermont 05405
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The effects of pharmacological activation and
inhibition of protein kinase C (PKC) and temperature on the
relationship between cytoplasmic
Ca2+ and lumen diameter were
studied in pressurized (50 mmHg) rat posterior cerebral arteries
permeabilized with 
-toxin. Increasing Ca2+ concentrations (30 nM-10
µM, 22°C) induced stable, concentration-dependent constrictions
with a half-maximal effective concentration
(EC50) of 112 nM. The maximal
constriction was 80% of baseline diameter and 157% of that during
depolarization of nonpermeabilized vessels with 124 mM KCl. Elevation
of temperature to 37°C increased the EC50 to 246 nM and enhanced the
steepness of concentration-response curves. Exposure of permeabilized
arteries to indolactam V, an activator of PKC, resulted in a
significant myofilament Ca2+
sensitization (e.g., EC50 at 5 µM = 126 nM) without changing efficacy. The effects of calphostin C,
a PKC inhibitor, on Ca2+
sensitivity were minimal; however, the amplitude of
Ca2+-induced constrictions in both
control and indolactam-treated arteries was suppressed in a
concentration-dependent manner. Thus 1) temperature is an important
variable in studies of arterial Ca2+ sensitivity, and
2) changes in PKC activity can
significantly alter both myofilament sensitivity to and constrictor
efficacy of cytosolic Ca2+.
-toxin permeabilized arteries; (
)-indolactam V; calphostin C; calcium ion
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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CYTOSOLIC Ca2+ concentration ([Ca2+]i) is an important determinant of vascular smooth muscle contractility. An elevation of the [Ca2+]i level due to influx of Ca2+ from the extracellular space, or its release from internal stores, is a pivotal mechanism for initiating smooth muscle contraction (17, 22, 37). The exact role of Ca2+ in regulating myofilament interactions during tonic contraction, however, still remains unclear, and new regulatory mechanisms in addition to Ca2+-dependent phosphorylation of myosin light chain kinase have been proposed (17).
The concept that protein kinase C (PKC) plays a role in tonic contraction of smooth muscle is relatively recent and came originally from observations that phorbol esters, established activators of PKC, can produce slowly developing sustained contraction in a number of vascular and nonvascular tissues. The Ca2+ requirement for this contraction varied greatly from tissue to tissue and, in some cases, occurred under Ca2+-free conditions (2, 10, 14, 17, 22, 26, 36). A temporal pattern of elevation in cytosolic diacylglycerol (DAG), an endogenous activator of PKC, or of PKC translocation from cytosol to membrane, correlates well with changes in agonist- or phorbol ester-induced force (2, 14, 17). Specific inhibitors of PKC have been shown to be more potent in suppressing agonist- rather than potassium-induced contractions, suggesting that increased activity of PKC might be an important determinant of agonist-induced, maintained contraction (35). However, in spite of an increasing body of evidence in favor of PKC involvement in the regulation of tonic smooth muscle contraction, the actual mechanisms remain largely unknown.
In some vascular smooth muscle preparations, phorbol ester-induced contraction was associated with an increased influx of Ca2+ into cells (17, 22). It has been reported that PKC activation resulted in inhibition of Ca2+-activated, ATP-sensitive, or voltage-dependent K+ channels (3, 6, 25, 34). In vascular smooth muscle cells (SMCs) K+ channels are important regulators of membrane potential. PKC-induced inhibition of K+ channels would therefore lead to membrane depolarization, thereby increasing Ca2+ influx through voltage-dependent Ca2+ channels. PKC can also augment Ca2+ entry in vascular SMCs by directly affecting L-type Ca2+ channel activity (11, 16). Phorbol esters and DAG analogs can produce additional contraction in permeabilized SMCs at fixed levels of Ca2+, suggesting that PKC can modulate the Ca2+ sensitivity of myofilament interactions (17, 28, 32).
There is indirect evidence that PKC plays an important role in
regulating cerebrovascular tone. Phorbol esters induced a sustained contraction of cerebral arteries that is associated with translocation of PKC from the cytosolic to membrane fraction (10, 26, 39). Membrane-bound PKC activity is also augmented during agonist-induced contraction and cerebral vasospasm (10, 23, 29). In our previous study,
we demonstrated that activation of PKC by indolactam V produced a
severe constriction of pressurized cerebral arteries that may, at least
in part, be related to sensitization of myofilaments to
Ca2+ (31). Therefore, our main
objectives in this study were to first establish the relationship
between intracellular Ca2+
concentration and cerebral artery lumen diameter and to then determine
how changes in temperature and PKC activation/inhibition affect the
Ca2+-diameter relationship. All
studies were performed in pressurized vessels permeabilized with
Staphylococcus aureus -toxin.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Animals and preparation of arteries. Adult (16- to 24-wk-old) male normotensive Wistar-Kyoto rats were anesthetized by an intraperitoneal injection of methohexital sodium (Brevital; 50 mg/kg) and killed by decapitation. The brain was removed and immersed in a dissection dish filled with HEPES-buffered physiological saline solution (HEPES-PSS, pH = 7.4). The entire posterior cerebral artery, including its branches, was removed and carefully dissected from surrounding connective tissues under a stereoscopic microscope. Small arterial segments 0.5-1.0 mm long were prepared from tertiary branches of the artery and transferred to the experimental chamber of an arteriograph filled with Ca2+-free relaxing solution. One end of the arterial segment was cannulated and secured on a glass cannula with single strands (20 µm) teased apart from a 1-cm length of a braided silk suture. After the vessel lumen was flushed gently with relaxing solution, the distal end of the segment was tied onto the second cannula, and intraluminal pressure was set to 50 mmHg using a pressure servo-system. A dual-chamber arteriograph containing two cannulated arterial segments was placed onto the stage of an inverted microscope with a monochrome video camera attached to a viewing tube and equilibrated at room temperature for 30 min in relaxing solution. Detailed descriptions of the pressurizing and lumen diameter analyzing systems have previously been published (30).
Experimental protocol. Preliminary
experiments were first run to determine the optimal time for successful
permeabilization of vascular SMCs by exposing pressurized arterial
segments to -toxin in the presence of 1.0 µM
Ca2+ (activating solution). This
allowed us to observe indirectly the process and effects of
permeabilization as evidenced by the rate, pattern, and degree of
constriction.
In subsequent experiments, permeabilization was always performed in
relaxing solution by a 20-min exposure to 800 U/ml of -toxin.
Arterial segments were then rinsed with relaxing solution two to three
times to remove any toxin from the bath solution. Vessels were
reequilibrated for 30 min, and constrictor responses to different
concentrations of Ca2+ were
obtained in a cumulative fashion by applying each dose of Ca2+ until arterial diameter
attained a steady-state level (usually 5-10 min). Only one
concentration-response curve was constructed for each artery segment,
as probe experiments revealed some hysteresis to low and intermediate
concentrations of Ca2+. To
minimize potential involvement of internal
Ca2+ stores, all experiments were
carried out in the presence of 10 µM ryanodine; application of
caffeine (10-20 mM) at the beginning of each experiment failed to
produce any constriction in relaxing solution containing ryanodine.
Although permeabilization with -toxin was always performed at room
temperature, Ca2+
concentration-response curves were obtained at room
temperature, and also at 37°C. For this purpose, the
temperature of the solution in the experimental chamber was increased
during 10-15 min by elevating the temperature of water flowing
through the water jacket. The equilibration period between washout of
-toxin and Ca2+ response curves
was kept constant (30 min) in all experiments. During this period,
arterial segments were warmed to 37°C and, where appropriate,
pretreated with an activator (indolactam) or inhibitor (calphostin C)
of PKC for 10 and 20 min, respectively.
Solutions and drugs. HEPES-PSS was of the following composition (in mM): 141.8 NaCl, 4.7 KCl, 1.7 MgSO4, 0.5 EDTA, 2.8 CaCl2, 1.2 KH2PO4, 10.0 HEPES, and 5.0 glucose (pH = 7.4). Relaxing Ca2+-free solution contained the following (free concentrations reported in mM): 63.6 potassium methanesulfonate (KMS), 2.0 MgCl2, 4.5 MgATP, 2.0 EGTA, 10.0 phosphocreatine, and 30.0 piperazine-N,N'-bis(2-ethanesulfonic acid). pH was adjusted to 7.1 with 10.0 N KOH. The composition of activating solution was similar to that of relaxing solution, except that it contained 10.0 mM EGTA, and a specified amount of CaCl2 was added to give the desired free Ca2+ concentration. The specific concentrations of reagents required to produce the desired free ionic concentrations were calculated by a computer program that solves a set of simultaneous equations describing the multiple equilibria of ions in solution (1). Both relaxing and activating solutions contained 1.0 µM carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), a mitochondrial blocker, 1.0 µM leupeptin, a protease inhibitor, and 10.0 µM ryanodine. Ionic strength was kept constant at 200 mM by adjusting the concentration of KMS.
Unless otherwise mentioned, all chemicals were purchased from Sigma
Chemical (St. Louis, MO). Staphylococcus
aureus -toxin, ()-indolactam V, ryanodine, and
calphostin C were obtained from Calbiochem (La Jolla, CA). Lyophilized
-toxin was reconstituted in deionized water to yield a stock
solution of 12,500 hemolytic U/ml and either used on the same day or
frozen (20°C) and used on the next experimental day.
Indolactam V, ryanodine, and FCCP were prepared as 10 mM stock
solutions in alcohol. Calphostin C was solubilized in dimethyl
sulfoxide to yield a 0.1 mM stock solution and was kept refrigerated in
the dark. Caffeine was dissolved directly in relaxing solution just
before use.
Statistical analysis. Data are expressed as means ± SE, where each n is the number of arterial segments studied. Ca2+-induced constriction was expressed as a percentage of maximum effect (sensitivity) or a percentage of maximum arterial diameter (efficacy) in relaxing solution. Student's t-test or ANOVA was used to determine the significance of differences between sets of data, considered significant at P < 0.05.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Ca2+-diameter
relationship in pressurized cerebral arteries permeabilized with
-toxin.
Figure 1A illustrates
a successful permeabilization with -toxin in one of our preliminary
experiments. Treatment of arterial segments with high (124 mM)-KCl
solution at room temperature induced a constriction to 51 ± 4%
(n = 4) of the baseline lumen
diameter. After washout of high-KCl solution, the HEPES-PSS within the
experimental chamber was substituted with an activating solution
containing 1.0 µM (pCa = 6.0)
Ca2+ and a high concentration of
K+ (~160 mM) to mimic the ionic
composition of cytosol. As a result, SMCs in the arterial wall undergo
depolarization. In the first 2-3 min after substitution of
HEPES-PSS with activating solution, the concentration of
Ca2+ in the vessel wall was still
high, and a transient constriction of the artery was observed. However,
continuous exposure of intact (nonpermeabilized) arteries to activating
solution containing 1.0 µM Ca2+ did not produce sustained
constriction (Fig. 1A).
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-toxin (800 hemolytic U/ml) into the experimental
chamber was followed by a slowly developing constriction that reached a
maximum in 15-20 min and was maintained until washout with
Ca2+-free relaxing solution. The
maximum value of the -toxin-induced constriction was 80 ± 2% of
baseline diameter or 157% of maximum K+-evoked responses at room
temperature. As is evident from the original recordings (Fig.
1C), -toxin-induced constriction
could be reversed by washout of the artery with
Ca2+-free relaxing solution. A
second application of activating solution (pCa = 6.0; 1.0 µM
Ca2+) in the absence of
-toxin produced the same decrease in arterial diameter,
demonstrating successful permeabilization of the SMCs.
In preliminary experiments, application of activating solutions with
high concentrations of Ca2+
(1-10 µM) decreased the
Ca2+ sensitivity of permeabilized
arterial SMCs. Therefore, to study the
Ca2+-diameter relationship in
subsequent experiments, permeabilization with -toxin was performed
in Ca2+-free relaxing solution.
After permeabilization (20 min) and an equilibration period of 30 min,
the concentration of Ca2+ within
the experimental chamber was increased cumulatively. Elevation of
Ca2+ was followed by a
concentration-dependent constriction of arteries, with a minimal effect
first observed at pCa = 7.25 (56 nM), while maximal constriction
occurred at pCa = 6.0 (1.0 µM). The pCa half-maximal effective
concentration (EC50) calculated
for each dose-response curve was 6.95 ± 0.05 (EC50 = 112 nM).
Effects of temperature on the Ca2+-diameter relationship. Cumulative addition of Ca2+ was followed by concentration-dependent, graded arterial constriction. The concentration of Ca2+ required to produce a detectable constriction was higher in warmed arteries (pCa = 7.0, 100 nM Ca2+) than in arteries at room temperature (pCa = 7.25, 56 nM Ca2+), although maximal constriction occurred at the same concentration of Ca2+ (pCa = 6.0, 1.0 µM Ca2+). Therefore, the concentration-response curve for Ca2+-induced changes in lumen diameter was steeper at 37°C (Fig. 2). The pCa EC50 for Ca2+-induced constriction at room temperature was 6.95 ± 0.05 (112 nM Ca2+), which is significantly less than the pCa EC50 (6.61 ± 0.03, 246 nM Ca2+) for warmed arteries (P < 0.05), indicating desensitization.
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PKC: Modulation of the Ca2+-diameter relationship by indolactam. The next series of experiments was designed to clarify the influence of PKC on myofilament Ca2+ sensitivity. For this purpose, we used indolactam V and calphostin C, compounds that selectively activate and inhibit PKC, respectively (12, 21). Previous experiments have shown that indolactam V induced a constriction of pressurized rat cerebral arteries (31). To test whether this constriction was at least partially induced by an enhanced myofilament Ca2+ sensitivity, we studied the effect of indolactam on the Ca2+-diameter relationship in permeabilized vessels. In Ca2+-free relaxing solution, indolactam produced only slight decreases in arterial diameter, 1.5 ± 0.6 and 4.6 ± 0.7% of baseline diameter for 0.1 and 5.0 µM indolactam, respectively. Application of 30 nM Ca2+ (pCa = 7.5) failed to evoke any additional constriction. Further increases in the concentration of Ca2+ resulted in dose-dependent constriction (Fig. 3B). Indolactam (0.1 and 5.0 µM) significantly shifted the dose-response curves to the left and decreased the pCa EC50 value from 6.61 ± 0.03 (246 nM Ca2+, control) to 6.82 ± 0.03 (159 nM Ca2+) and 6.92 ± 0.03 (126 nM Ca2+; Fig. 4).
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Effects of calphostin C on the Ca2+-diameter relationship. Permeabilized arteries were pretreated with calphostin C for 15-20 min at 37°C. Figure 5 demonstrates the concentration-response curves for Ca2+-induced constriction obtained at three different concentrations (10, 30, and 100 nM). Calphostin C decreased the amplitude of Ca2+-induced constrictions at any given concentration of Ca2+ in a concentration-dependent manner, as well as the maximal response. Sensitivity was unchanged, however, except at the highest concentration (100 nM), in which sensitivity was somewhat enhanced (EC50, see Fig. 5).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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This study investigated the relationship between cytoplasmic
Ca2+ concentrations and magnitude
of constriction in small pressurized cerebral arteries. Vessels were
permeabilized with -toxin, a protein that inserts into the lipid
bilayer of plasma membranes to form heptameric transmembrane pores
2-3 nm in diameter (13). Their small size allows free movement of
water, ions, and molecules having molecular masses <1,000 kDa,
whereas larger protein molecules (calmodulin, PKC) important to the
regulation of myofilament interaction remain within the cells (20, 27).
Ca2+
sensitivity: control vessels.
We did not observe any significant constriction of arteries at
Ca2+ concentrations <100 nM (pCa = 7.0; 37°C). These data are in good agreement with fura 2 measurements of cytoplasmic Ca2+
levels (50-100 nM) in smooth muscle of unstimulated arteries (8,
24). The EC50 values calculated
for cerebral arteries in our study (112 nM, 22°C and 246 nM,
37°C) were significantly lower than those reported for the
Ca2+-isometric force relationship
in femoral, pulmonary (
300 nM, 25°C; see Ref. 19), and
mesenteric arteries (630 nM, 37°C; see Ref. 28). The heightened
Ca2+ sensitivity demonstrated in
our experiments might be related to differences in isometric
preparations versus pressurized arteries, as previously reported for
intact vessels in which sensitivity to constrictor agents was
significantly greater in pressurized vs. wire-mounted arteries (5, 9).
The Ca2+-diameter curves in
cerebral arteries were remarkably steep such that the entire range of
constriction was observed over a very narrow range of
Ca2+ concentrations (100-300
nM). This observation suggests that relatively small changes in
cytoplasmic Ca2+ levels can exert
substantial effects on cerebral artery lumen diameter.
)-indolactam V, a
synthetic alkaloid related to the tumor promoter teleocidin (12).
Indolactam binds to PKC and has biological properties similar to
tumor-promoting phorbol esters that are commonly used to activate PKC
(18). Like DAG, indolactam shows equal affinity in binding to different
isozymes of PKC and has been used in a number of previous studies of
PKC modulation of cell function (16, 18, 31).
In relaxing Ca2+-free solution,
activation of PKC by indolactam slightly decreased the diameter of
permeabilized arteries. Elevation of
Ca2+ concentrations to 50 nM did
not result in any additional constriction, suggesting that this effect,
while minor, was the result of
Ca2+-independent mechanisms. At
higher Ca2+ concentrations,
indolactam increased the Ca2+
sensitivity of the contractile process, as evidenced by the parallel leftward shift of the
Ca2+-diameter relationship, in a
concentration-dependent manner. The magnitude of this effect was
substantial; for example, indolactam (5.0 µM) increased constriction
to an intermediate concentration of
Ca2+ (100 nM) fivefold. Thus it is
clear that activation of PKC can induce significant cerebral artery
constriction without any changes in cytoplasmic
Ca2+. It was difficult to evaluate
its effect on efficacy, however, since high concentrations of
Ca2+ produced maximal
constrictions on their own, with >85% reductions in diameter, i.e.,
almost complete closure of the lumen.
Indolactam-induced activation of PKC in mesenteric arteries was
associated with enhancement of myosin light chain phosphorylation, a
proposed target for PKC in this tissue (16). Whether this also applies
to small cerebral arteries remains unclear; in larger cerebral
arteries, phorbol ester-evoked constriction occurred without a
concurrent increase in myosin light chain phosphorylation, indicating
the involvement of some unidentified mechanism(s) for myofilament
interaction (26, 39).
Both staurosporine (31) and calphostin C, a microbial compound isolated
from Cladosporium cladosporioides,
inhibit myogenic tone in intact cerebral arteries
(EC50 = 15 nM for
calphostin C, data not shown). Unlike staurosporine or H-7, which bind
to the catalytic domain of PKC, calphostin C interacts with DAG-binding sites in the regulatory domain, thereby conferring much greater selectivity (21) that argues in favor of a specific effect on PKC
activity, rather than that of other kinases.
In addition to its effects on PKC, calphostin C also inhibits L-type
Ca2+ channels of myocardial cells
(15). If this effect occurs in vascular smooth muscle, vasodilation
unrelated to PKC would be anticipated. The use of permeabilized vessels
allowed us to examine the effects of calphostin C in the absence of
membrane potential and channel activity and thereby avoid this
potential complication. As shown in RESULTS, calphostin C
effectively and potently decreased constriction of permeabilized
arteries to a given concentration of
Ca2+, suggesting that its effect
on arterial contractility is not limited to membrane-related actions
and therefore is likely to involve PKC.
An unexpected observation was the ability of calphostin C to inhibit
subsequent constriction to Ca2+
without the addition of indolactam, suggesting that PKC is partially activated in pressurized cerebral arteries permeabilized with -toxin, as well as in intact arteries. Whether this enhancement in
PKC activity is induced by intraluminal pressure remains to be
determined.
Unlike indolactam, calphostin C (10 and 30 nM) did not alter the
sensitivity of vessels to Ca2+, as
EC50 values were unchanged in its
presence. The highest concentration used (100 nM) eliminated virtually
all constriction, even at high Ca2+ concentrations. Plotted as
sensitivity, these data suggest that calphostin C increased arterial
sensitivity to Ca2+. Considering
the extensive suppression of constriction, however, we feel that this
association may be artifactual and is difficult to interpret from a
mechanistic standpoint.
Conversely, calphostin C clearly suppressed the maximal
Ca2+-induced constriction in both
control and indolactam-pretreated arteries. A decrease in efficacy
without any change in sensitivity has been reported for the effects of
another PKC inhibitor on the
Ca2+-force relationship in
isolated SMCs from ferret aorta (4). The 17-kDa peptide inhibitor used
in that study was highly specific for PKC and was interpreted by the
authors as evidence that vascular smooth muscle PKC is functionally
Ca2+ independent, at least in the
ferret aorta (4). This rationale is difficult to apply to the findings
in this study, as the
Ca2+-independent effects of PKC
activation were just above the level of detection. An intermediate
concentration of calphostin C (30 nM) did significantly inhibit the
effects of indolactam, however, as would be predicted by the respective
actions of these compounds on PKC.
In conclusion, pharmacological manipulation of PKC activity can
profoundly alter both myofilament sensitivity to and constrictor efficacy of cytosolic Ca2+ in
small cerebral arteries. Its effects in vitro result in substantial changes in arterial lumen diameter, a principal determinant of blood
flow under normal conditions. The precise mechanisms by which PKC
modulates contractile protein interaction in cerebral artery vascular
smooth muscle, as well as its role in physiological and
pathophysiological regulation of cerebrovascular tone, remain to be
determined.
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ACKNOWLEDGEMENTS |
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This work was supported by Grant-in-Aid 93014090 from the American Heart Association.
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FOOTNOTES |
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Address for reprint requests: N. I. Gokina, Dept. of Obstetrics and Gynecology, The Univ. of Vermont, College of Medicine, Burlington, VT 05405.
Received 29 December 1997; accepted in final form 5 February 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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