Oxytocin increases the
[Ca2+]i
sensitivity of human myometrium during the falling phase of phasic
contractions
Keena
McKillen1,2,
Steven
Thornton3, and
Colin W.
Taylor1
1 Department of Pharmacology, University of
Cambridge, Cambridge CB2 1QJ; 2 Department of
Obstetrics and Gynaecology, University of Cambridge, Rosie Hospital,
Cambridge CB2 2SW; and 3 Department of Biological
Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom
 |
ABSTRACT |
Oxytocin is commonly used to induce or augment
labor, but its mode of action is uncertain. To address the issue,
isometric tension and the intracellular free
Ca2+ concentration
([Ca2+]i)
were simultaneously recorded from isolated strips of pregnant human
myometrium loaded with fura 2. The changes in
[Ca2+]i
and tension during phasic contractions were indistinguishable in
myometrium taken before or after the onset of labor, enabling samples
to be pooled. Oxytocin (10 nM) had no effect on basal [Ca2+]i
or tension, but it increased both the
[Ca2+]i
and the tension recorded during phasic contractions. Analysis of the
[Ca2+]i-tension
relationship revealed that during the falling (relaxation) phase of the
contractile response, oxytocin increased the tension recorded at each
[Ca2+]i.
By manipulating extracellular Ca2+
during phasic contractions, it was possible to ensure that the [Ca2+]i
signals were similar in the presence and absence of oxytocin, yet
oxytocin still improved the
[Ca2+]i-tension
relationship. We conclude that 10 nM oxytocin increases the
[Ca2+]i
sensitivity of the contractile proteins only after a contraction has
begun, possibly by causing inhibition of myosin light chain phosphatase.
smooth muscle; signal transduction; labor; pregnancy; uterus
 |
INTRODUCTION |
OXYTOCIN INCREASES the force and duration of myometrial
contractions and is used clinically for induction and augmentation of
labor. Whether endogenous oxytocin is involved in the onset and
progression of normal human labor is controversial (27). Neither the
maternal nor fetal plasma oxytocin concentrations have been
conclusively demonstrated to increase during labor (27). However, the
sensitivity of the uterus to oxytocin increases during pregnancy (2),
and oxytocin antagonists reduce the frequency of spontaneous
contractions (5).
Oxytocin interacts with a member of the family of receptors that couple
to G proteins and thereby stimulates, via Gq/11 and possibly Gh, phospholipase
C-mediated hydrolysis of polyphosphoinositides (10, 15, 17). The links
between this or indeed other signalling pathways activated by oxytocin
(14) and myometrial contractility are ill defined: they may involve
regulation of both the intracellular free
Ca2+ concentration
([Ca2+]i)
and the Ca2+ sensitivity of the
contractile machinery.
In common with other smooth muscles (23), myometrial contractions are
associated with increases in
[Ca2+]i
(30). Ca2+ bound to calmodulin
activates myosin light chain kinase, which then phosphorylates the
regulatory myosin light chains, allowing them to rapidly bind to and
detach from actin filaments and so generate tension. Although an
increase in
[Ca2+]i
is a major control of smooth muscle contraction, hormones can also
enhance contractile activity without directly increasing [Ca2+]i
(29). Inhibition of myosin phosphatase causing a decrease in the rate
of dephosphorylation of myosin light chain is a likely means of such
Ca2+ sensitization (22, 23, 28).
In permeabilized rat myometrium (8), oxytocin causes
Ca2+ sensitization, but results
from intact human tissue loaded with aequorin are contradictory (24).
The effects of oxytocin on spontaneously active myometrium have not yet
been examined under conditions that allow its influence on the
[Ca2+]i-tension
relationship to be defined.
In the present study, myometrium taken before or after the onset of
labor was loaded with fura 2, and the effects of oxytocin on the
[Ca2+]i-tension
relationship were examined by simultaneous measurement of tension and
[Ca2+]i
during phasic contractions.
 |
METHODS |
Simultaneous measurements of isometric tension and
[Ca2+]i.
Myometrial biopsies were obtained with informed written consent and
local ethical committee approval (LREC DEC 89/56) at term caesarean
section (37-42 wk gestation) either before or after the onset of
labor. Indications for caesarean section included noncephalic
presentation, previous caesarean section, failure to progress in labor,
or fetal distress. Women had no significant medical conditions, and
labor was defined as progressive (>2 cm) cervical dilation
accompanied by regular uterine contractions.
Small strips of myometrium (2 × 2 × 15 mm) were dissected
so that the longitudinal axis aligned with the direction of the muscle
fibers. Strips were incubated for 15 h at 20°C in Krebs-Henseleit solution (KHS) containing 50 µM fura 2-acetoxymethyl ester (Molecular Probes, Leiden, The Netherlands) dissolved in anhydrous dimethyl sulfoxide (10%) and pluronic acid (0.5%) and then were washed in KHS
(30 min). KHS, equilibrated with 5%
CO2-95%
O2, had the following composition
(in mM): 118 NaCl, 4.7 KCl, 1.2 CaCl2, 1.2 MgSO4, 25 NaH2CO3,
1.2 K2PO4,
and 11 glucose, pH 7.4. Strips were mounted (Fig.
1A) in
a polymethylacrylate cuvette within a Perkin-Elmer LS50B
spectrofluorimeter. One end of the muscle was attached by cotton to an
isometric tension recording system comprising a Fort-10 transducer
(World Precision Instruments, Aston, UK: bandwidth 0-10 g) and an
EpiCompact amplifier and data acquisition system (Cambridge Research
Systems, Cambridge, UK). A rapidly rotating filter wheel provided light
of appropriate excitation wavelength (340 and 380 nm), and emitted
light was collected through a long-pass barrier filter (510 nm).
Autofluorescence (<10% of the fluorescence recorded from strips
loaded with fura 2) was determined at the end of each experiment by
addition of MnCl2 (2 mM) and
ionomycin (5 µM) to quench the fura 2 fluorescence.
[Ca2+]i
was determined from the ratio of the corrected fluorescence at 340 and
380 nm (R340/380) using a
look-up table created from Ca2+
standard solutions obtained from Molecular Probes (12). The fluorescence ratio (R340/380)
and isometric tension were sampled simultaneously at 1 Hz (5 Hz for the
high-resolution recordings in Fig. 3).

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Fig. 1.
Simultaneous determination of intracellular free
Ca2+ concentration
([Ca2+]i)
and tension in spontaneously active myometrium.
A: myometrial strips attached to an
isometric force transducer were mounted in a perfused cuvette for
simultaneous determination of
[Ca2+]i
and tension. B: spontaneous
contractions of strips that had not been loaded with fura 2 were not
associated with changes in fluorescence ratio.
C: spontaneous changes in tension
(i) were associated with reciprocal
changes in the fluorescence recorded at 510 nm after excitation at 340 and 380 nm (ii). Fluorescence ratio
at 340 and 380 nm (R340/380;
iii) was used to determine the
[Ca2+]i
shown in all subsequent traces.
|
|
Before an experiment, muscle strips were superfused for 1 h
with KHS (~1 ml/min) at 37°C under 2 g of tension and then
were superfused continuously throughout the experiment. Strips that failed to spontaneously contract during the first hour were discarded. Exchanges of media were complete within 210 s, and contractions occurring within this time were excluded from subsequent analyses. Oxytocin acetate was obtained from Sigma (Poole, UK).
Analysis.
Results were corrected for
the small drift in basal tension and fluorescence ratio
in some of these protracted experiments. Integrated areas under the
curve (AUC) for
[Ca2+]i
and tension for each contraction were calculated using an Excel spreadsheet; AUC data therefore describe individual contractions and
are independent of their frequency. To allow direct analysis of the
[Ca2+]i-tension
relationship, each measurement of the increase in
[Ca2+]i
was plotted against the simultaneously recorded increase in isometric
tension. Each of these
[Ca2+]i-tension
plots therefore had a rising phase (to the peak
[Ca2+]i)
and a falling phase (as
[Ca2+]i
returned to baseline). To compare tissues from different patients, the
maximal separation (S) between the
rising and falling phases of these plots was used as an index of the
extent to which oxytocin selectively affects the falling phase of the
[Ca2+]i-tension
relationship (see RESULTS).
Unless otherwise stated, only a single strip from each patient was
included in the final analysis. Results are presented as means ± SE. Statistical analyses employed the Mann-Whitney
U-test and Student's
t-test, with
P < 0.05 taken as significant.
 |
RESULTS |
[Ca2+]i
and tension in spontaneously active myometrium taken before or after
the onset of labor.
Although myometrial strips are intrinsically fluorescent at the
wavelengths used to record fura 2 fluorescence, our results demonstrate
that it is possible to simultaneously measure tension and
[Ca2+]i.
First, the fluorescence ratio of strips that had not been loaded with
fura 2 was unaffected by contractions (Fig.
1B). Second, only muscles in which
contractions were accompanied by reciprocal changes in the fura 2 fluorescence recorded at the two excitation wavelengths (340 and 380 nm) were analyzed (Fig. 1C). Third,
in paired comparisons of myometrial strips (24 from 3 patients), fura 2 loading had no effect on spontaneous contractile activity: 11 of the 12 fura 2-loaded strips and 9 of the 12 control strips were spontaneously
contractile; the peak tension (113 ± 39% of control,
P > 0.05), frequency of contractions
(109 ± 9%, P > 0.05), and AUC (130 ± 44%, P > 0.05)
were all similar under the two conditions. Removal of extracellular
Ca2+ or addition of nimodipine
(100 nM) abolished both spontaneous contractions and the changes in
fluorescence ratio (not shown), in keeping with previous reports (6).
Comparison of the changes in
[Ca2+]i
and tension recorded during spontaneous contractions (60 min) of muscle
strips taken before or after the onset of labor (Fig.
2) revealed no significant differences, nor
were the effects of oxytocin different between the two samples (Table
1). Therefore, in all subsequent
experiments, biopsies taken from patients before and after the onset of
labor were pooled.

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Fig. 2.
Simultaneous changes in
[Ca2+]i
and tension during spontaneous contractions of myometrial strips taken
before (A) and after
(B) the onset of labor. Recordings
are typical of those from 11 (A) and
6 (B) patients.
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To better resolve the temporal relationship between changes in
[Ca2+]i
and tension during spontaneous contractions, recordings were made at 5 Hz. The increase in
[Ca2+]i
preceded the increase in tension (Fig. 3)
by 436 ± 89 ms (n = 11) at the
onset of a contraction and by 13 ± 3 s
(n = 17) at its peak. These
substantial delays, reflecting the cascade of biochemical events
separating an increase in
[Ca2+]i
from contraction, are similar to those observed in other smooth muscles
(23, 31).

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Fig. 3.
Temporal relationship between
[Ca2+]i
and tension during spontaneous contractions.
A: high-resolution recording (5 Hz) of
a single spontaneous contraction of myometrium demonstrates that the
increase in
[Ca2+]i
precedes tension. B: rising phase of
the contraction shown on an expanded scale. Results are typical of
those from 11 patients.
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|
Our results establish that spontaneous contractile activity is
dependent on Ca2+ entry through
L-type Ca2+ channels (19, 32),
that tissue taken before or after the onset of labor behaves similarly
(although loss of labor characteristics during fura 2 loading cannot be
excluded), and that fura 2 can be used to measure
[Ca2+]i
in myometrium without interfering with its contractile activity.
Effect of oxytocin on phasic
contractions. Because the half-maximal effect of
oxytocin on myometrial contractility occurs when its concentration is
~10 nM (24, 26), this concentration was used in all subsequent
experiments. Oxytocin had no significant effect on basal
[Ca2+]i
or tension (Fig. 4):
in paired comparisons of measurements during the first
(pretreatment) and second (±oxytocin) hour of phasic contractile
activity, the basal
[Ca2+]i
and tension responses recorded from muscles stimulated with oxytocin
were 98 ± 3 and 96 ± 3% (n = 11, P > 0.05 for each) of control
responses, respectively. Control samples
(n = 4) were not treated with oxytocin
during the second hour to account for time-dependent changes in
activity. Oxytocin did, however, increase the magnitude of both the
tension and
[Ca2+]i
recorded during phasic contractions (Fig.
5). Oxytocin had no significant effect on
the frequency of contractions (7.7 ± 1.7 and 5.1 ± 0.8 h
1 before and after
oxytocin, respectively, P > 0.05, n = 11), consistent with previous
studies of myometrium in vitro (24). Because oxytocin more markedly
increased tension than
[Ca2+]i,
the relationship between
[Ca2+]i
and tension was examined in detail.

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Fig. 4.
Effects of oxytocin on
[Ca2+]i
and tension during phasic contractions. Spontaneous contractions were
recorded for 1 h (A) and from the
same strip during a second hour in the presence of oxytocin
(B). Results are typical of those
from at least 11 patients, the results of which are summarized in Table
1.
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Fig. 5.
Effects of oxytocin on peak
[Ca2+]i
(A) and area under the curve (AUC;
B) for
[Ca2+]i
and tension during phasic contractions. From experiments similar to
those depicted in Fig. 4, the mean responses recorded during the second
hour were expressed as percentages of those in the first hour. Filled
bars, strips stimulated with oxytocin in the second hour
(n = 11 patients); open bars, control
strips (n = 4 patients).
* P < 0.05.
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Figure 6 shows the instantaneous
relationship between
[Ca2+]i
and tension during phasic contractions in the presence and absence of
oxytocin. In both cases, the relationships are strikingly asymmetric and comprise a rising phase during which tension is less sensitive to
[Ca2+]i
than during the subsequent falling phase (Fig. 3), consistent with slow
steps linking Ca2+ to contraction
(31). Oxytocin had no effect on the rising phase of the
[Ca2+]i-tension
relationship but significantly affected the falling phase such that at
each
[Ca2+]i
there was a greater increase in tension (Fig. 6,
B and
D). To accommodate the variability
between tissues from different patients (24) and yet allow quantitative
analysis of the effects of oxytocin on the
[Ca2+]i-tension
relationship, we adopted the following analysis. The average
half-maximal increase in
[Ca2+]i
for all muscle strips was 39 nM, and the tension recorded at this
[Ca2+]i
was therefore compared on the rising and falling phases of the
[Ca2+]i-tension
relationship. Comparison of these values from the last contraction
before oxytocin addition with the first after its addition demonstrates
that oxytocin significantly increases the tension only during the
falling phase of the response (Table 2).

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Fig. 6.
Effects of oxytocin on
[Ca2+]i-tension
relationship.
[Ca2+]i
and tension during sequential contractions of the same myometrial strip
were recorded before (A) or after
(C) addition of oxytocin.
Instantaneous relationship between increase in
[Ca2+]i
and tension is shown, with the arrows depicting rising and falling
phases of the responses (B and
D). Maximal separation,
S, used in subsequent analyses is
indicated by the double-headed arrow. Results are typical of those from
at least 8 patients, the results of which are summarized in Table 2.
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A simple means of examining changes in the
[Ca2+]i-tension
relationship is provided by quantifying the maximal
S of the rising and falling phases of
the response (see METHODS). To eliminate problems resulting
from slow changes in muscle properties during our protracted
recordings,
[Ca2+]i-tension
relationships were plotted for each contraction,
S was calculated for each contraction
during 2 h of activity, and S values
were then expressed as percentages of the preceding contraction (Fig.
7). This form of analysis was applied to
control myometrial strips and those treated with oxytocin (10 nM) for
the second hour of phasic activity. The results demonstrate that there
is no change in the S of the
[Ca2+]i-tension
relationship between sequential control contractions but that, after
oxytocin addition, the S abruptly
increases and is thereafter maintained throughout the period of
stimulation with oxytocin (Fig. 7).

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Fig. 7.
Oxytocin increases S between the
rising and falling phases of the
[Ca2+]i-tension
relationship.
[Ca2+]i-tension
plots, similar to those in Fig. 6, were used to define the maximal
S for each contraction. Figure shows
S expressed as a percentage of that
from the previous contraction, i.e.,
S2/S1
(inset); 100% therefore indicates
that S was the same in successive
contractions. Filled bars, strips treated with oxytocin during the
second hour (n = 8 patients); open
bars, control strips (n = 4 patients).
Results demonstrate that S is stable
between successive contractions and significantly
(* P < 0.05) increases only
when oxytocin is applied (juncture between the first and second
hour).
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Oxytocin increases the
Ca2+ sensitivity
of the contractile machinery.
The results are so far consistent with oxytocin selectively increasing
the Ca2+ sensitivity of the
contractile apparatus during the falling phase of the contractile
response. However, oxytocin also significantly increased the duration
of the increase in
[Ca2+]i
(and thereby the AUC), and this effect may have contributed to the
change in the
[Ca2+]i-tension
relationship (Figs. 5 and 6C and Table
1). To resolve the issue,
[Ca2+]i
transients of similar duration were produced in the presence and
absence of oxytocin by rapidly chelating extracellular
Ca2+ using EGTA during the rising
phase of a phasic contraction (Fig. 8).
Under these conditions, the
[Ca2+]i
AUC was similar for control and oxytocin-treated muscle (107 ± 18%
of control, n = 5, P > 0.05), and the rate at
which
[Ca2+]i
monoexponentially returned to baseline was indistinguishable (time
constant 18 ± 4 and 19 ± 4 s for control and oxytocin treated, respectively). Despite the similar
Ca2+ signals, oxytocin still
caused an increase in the tension recorded during a phasic contraction.
In the presence of oxytocin, the peak and AUC tension were increased to
159 ± 13% (n = 5, P < 0.01) and 177 ± 31%
(n = 5, P > 0.05) of their control values,
and from the
[Ca2+]i-tension
relationship, oxytocin increased S to
203 ± 15% (n = 5, P < 0.05) of its pretreatment value
(Fig. 8). These results establish that oxytocin increases the
Ca2+ sensitivity of the
contractile apparatus during phasic contractions independent of its
ability to enhance the increase in
[Ca2+]i.

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Fig. 8.
Oxytocin increases the
[Ca2+]i
sensitivity independent upon its effect on
[Ca2+]i.
Contractions were recorded in the absence
(A) or presence
(C) of oxytocin, and extracellular
Ca2+ was reduced rapidly during
the subsequent contraction to ensure that the
[Ca2+]i
signals were similar irrespective of the presence of oxytocin.
Resulting
[Ca2+]i-tension
plots (B and
D) demonstrate that oxytocin retains
its ability to increase the
[Ca2+]i
sensitivity of the falling phase of the response independent of its
ability to prolong the
[Ca2+]i
signal. ,
[Ca2+]i-tension
relationship in Krebs-Henseleit solution; , responses when
extracellular Ca2+ was rapidly
removed during contraction. Results are typical of 5 similar
experiments. Some symbols have been omitted from the
[Ca2+]i-tension
plots (B and
D) for clarity.
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 |
DISCUSSION |
In the only previous simultaneous measurements of
[Ca2+]i
and tension in human myometrium, the luminescent indicator aequorin was
used (24). This indicator has several limitations: the membrane must be
transiently permeabilized to allow loading, it is difficult to
calibrate, and it is not amenable to the protracted recording required
for multiple measurements from a single strip. Fura 2, which has been
used in rat myometrium (18-20), overcomes these limitations, and
we have established that it can be used to quantify [Ca2+]i
in spontaneously active human myometrium without interfering with its
contractile behavior (Fig. 1).
Although labor is accompanied by profound changes in the physiology of
the myometrium (3, 4, 9), our results suggest that the
Ca2+ sensitivity of the
contractile apparatus does not change in fura 2-loaded strips (Table
1), consistent with results from skinned myometrium of the rat (7). We
cannot, however, entirely eliminate the possibility that some
differences between labor and nonlabor issues have been lost during the
15 h taken to load strips with fura 2.
Very high concentrations of oxytocin (µM) directly stimulate
increases in
[Ca2+]i
and thereby tonic contractions (13). In our experiments, the
characteristic phasic activity of normal myometrium (19, 30) was
maintained by using a lower concentration (10 nM) of oxytocin, and the
results pertain specifically to this concentration. Under these more
physiological conditions, our results reveal two distinct modulatory
effects of oxytocin on phasic activity.
First, oxytocin modestly increased the amplitude of the
Ca2+ signal recorded during each
spontaneous contraction (Table 1). We have not further addressed the
mechanisms underlying this potentiation of the
Ca2+ signals evoked by
Ca2+ entry through L-type
Ca2+ channels. The effect is not a
consequence of oxytocin inhibiting Ca2+ removal from the cytosol,
because after rapid removal of extracellular Ca2+, rates of
[Ca2+]i
recovery were unaffected by oxytocin (Fig. 8). In addition, it cannot
simply reflect release of Ca2+
stores by inositol 1,4,5-trisphosphate
(IP3) because, even during several hours of exposure to oxytocin (Fig. 4), its effects were manifest only during spontaneous contractions; neither basal tension nor
[Ca2+]i
was affected. IP3 receptors are
stimulated by the concerted actions of
IP3 and
Ca2+ (25), and oxytocin may
therefore have caused the formation of a subthreshold level of
IP3 such that the increase in
[Ca2+]i
after spontaneous opening of L-type
Ca2+ channels would synergize with
it to cause release of intracellular Ca2+ stores and so amplify the
Ca2+ signal. Alternatively,
oxytocin, possibly via protein kinase C (16), may have increased the
sensitivity of the L-type Ca2+
channels (11).
The second, and more striking, effect of this concentration of oxytocin
was to selectively increase the tension evoked at each
[Ca2+]i
during the falling phase of each phasic contraction (Table 2). The only
previous simultaneous measurements of
[Ca2+]i
and tension in pregnant human myometrium concluded that oxytocin had no
effect on the
[Ca2+]i-tension
relationship at either the peak of the response or during tonic
contractions (24). In our experiments, the effect of oxytocin on the
[Ca2+]i-tension
relationship of spontaneously active myometrium was independent of its
ability to prolong the Ca2+ signal
(Fig. 8). How might oxytocin, without directly increasing [Ca2+]i,
selectively increase the Ca2+
sensitivity of the contractile apparatus during only the later stages
of each phasic contraction?
Oxytocin stimulates the mitogen-activated protein kinase (MAPK) cascade
(14), and in some smooth muscles MAPK has been shown to phosphorylate
caldesmon (1), thereby increasing the
[Ca2+]i
sensitivity of the contractile apparatus (21). Such a mechanism would
not, however, readily explain why oxytocin increases the [Ca2+]i
sensitivity during only the falling phase of the response. A more
likely mechanism would involve inhibition of myosin light chain
phosphatase activity (23), the effect of which would be more pronounced
after substantial phosphorylation of myosin light chains. Rho and its
associated kinase (28), arachidonic acid, G proteins, and protein
kinase C (23) have each been implicated in linking receptors to
inhibition of myosin light chain phosphatase, but the links with the
oxytocin receptor remain to be defined.
We conclude that oxytocin selectively increases the
[Ca2+]i
sensitivity of the contractile apparatus during only the falling phase
of a contraction, possibly by inhibition of myosin phosphatase. Selective manipulation of the mechanisms responsible for the
[Ca2+]i
sensitization may ultimately provide additional means of controlling myometrial contractility for induction of labor or treatment of preterm labor.
 |
ACKNOWLEDGEMENTS |
We thank patients and staff of the Rosie Hospital, Cambridge, UK.
 |
FOOTNOTES |
This work was supported by The Sir Jules Thorn Charitable Trust. S. Thornton was a Medical Research Council Clinical Scientist.
Portions of this work were presented at the Physiological Society
meeting in Cambridge, UK, December 15-17, 1997, and at the Society
for Gynecologic Investigation in Atlanta, Georgia, March 11-14,
1998. The work has also been published as an abstract
(J. Physiol. 506: 144P, 1998 and
J. Soc. Gynecol. Invest. 5: 185A, 1998).
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: S. Thornton, Dept. of Biological
Sciences, University of Warwick, Coventry CV4 7AL, UK.
Received 27 July 1998; accepted in final form 13 October 1998.
 |
REFERENCES |
1.
Allen, B. G.,
and
M. P. Walsh.
The biochemical basis of the regulation of smooth-muscle contraction.
Trends Biochem. Sci.
19:
362-368,
1994[Medline].
2.
Embrey, M. P.,
and
J. C. Moir.
A comparison of the oxytocic effects of synthetic vasopressin and oxytocin.
J. Obstet. Gynaecol. Brit. Commwlth.
74:
648-651,
1967.
3.
Fuchs, A.-R.,
F. Fuchs,
P. Husslein,
M. S. Soloff,
and
M. J. Fernstrom.
Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor.
Science
215:
1396-1398,
1982[Medline].
4.
Garfield, R. E.,
and
R. H. Hayashi.
Appearance of gap junctions in the myometrium of women during labor.
Am. J. Obstet. Gynecol.
140:
254-260,
1981[Medline].
5.
Goodwin, T. M.,
R. Paul,
H. Silver,
W. Spellacy,
M. Parsons,
R. Chez,
R. Hayashi,
G. Valenzuela,
G. W. Creasy,
and
R. Merriman.
The effect of the oxytocin antagonist atosiban on preterm uterine activity in the human.
Am. J. Obstet. Gynecol.
170:
474-478,
1994[Medline].
6.
Hollingsworth, M.,
and
S. J. Downing.
Calcium entry blockers and the uterus.
Med. Sci. Res.
16:
1-6,
1988.
7.
Izumi, H.,
K. Bian,
R. D. Bukoski,
and
R. E Garfield.
Agonists increase the sensitivity of contractile elements for Ca++ in pregnant rat myometrium.
Am. J. Obstet. Gynecol.
175:
199-206,
1996[Medline].
8.
Izumi, H.,
J. Ichihara,
Y. Uchiumi,
and
K. Shirakawa.
Gestational changes in mechanical properties of skinned muscle tissues of human myometrium.
Am. J. Obstet. Gynecol.
163:
638-647,
1990[Medline].
9.
Khan, R. N.,
S. K. Smith,
J. J. Morrison,
and
M. L. J. Ashford.
Properties of large-conductance K+ channels in human myometrium during pregnancy and labour.
Proc. R. Soc. Lond. B. Biol. Sci.
251:
9-15,
1993[Medline].
10.
Ku, C. Y.,
A. Qian,
Y. Wen,
K. Anwer,
and
B. M. Sanborn.
Oxytocin stimulates myometrial guanosine triphosphatase and phospholipase-C activities via coupling to G
q/11.
Endocrinology
136:
1509-1515,
1995[Abstract].
11.
Kusaka, M.,
and
N. Sperelakis.
Stimulation of Ca2+ current by phorbol esters in rat myometrial cells is dependent on intracellular Ca2+ concentration.
Reprod. Fertil. Dev.
8:
1147-1152,
1996[Medline].
12.
Madge, L.,
I. C. Marshall,
and
C. W. Taylor.
Delayed autoregulation of the Ca2+ signals resulting from capacitative Ca2+ entry in bovine pulmonary artery endothelial cells.
J. Physiol. (Lond.)
498:
351-369,
1997[Abstract].
13.
Maggi, M.,
P. Del Carlo,
G. Fantoni,
S. Giannini,
C. Torrisi,
D. Casparis,
G. Massi,
and
M. Serio.
Human myometrium during pregnancy contains and responds to V1 vasopressin receptors as well as oxytocin receptors.
J. Clin. Endocrinol. Metab.
70:
1142-1154,
1990[Abstract].
14.
Ohmichi, M.,
K. Koike,
A. Nohara,
Y. Kanda,
Y. Sakamoto,
Z. X. Zhang,
K. Hirota,
and
A. Miyake.
Oxytocin stimulates mitogen-activated protein kinase activity in cultured human puerperal uterine myometrial cells.
Endocrinology
136:
2082-2087,
1995[Abstract].
15.
Park, E.-S.,
J. H. Won,
K. J. Han,
P.-G. Suh,
S. H. Ryu,
H. S. Lee,
H.-Y. Yun,
N. S. Kwon,
and
K. J. Baek.
Phospholipase C-
1 and oxytocin receptor signalling: evidence of its role as an effector.
Biochem. J.
331:
283-289,
1998[Medline].
16.
Phaneuf, S.,
M. P. Carrasco,
G. N. Europe-Finner,
C. H. Hamilton,
and
A. Lopez Bernal.
Multiple G proteins and phospholipase C isoforms in human myometrial cells: implication for oxytocin action.
J. Clin. Endocrinol. Metab.
81:
2098-2103,
1996[Abstract].
17.
Phaneuf, S.,
G. N. Europe-Finner,
M. Varney,
I. Z. MacKenzie,
S. P. Watson,
and
A. Lopez Bernal.
Oxytocin-stimulated phosphoinositide hydrolysis in human myometrial cells: involvement of pertussis toxin-sensitive and -insensitive G-proteins.
J. Endocrinol.
136:
497-509,
1993[Abstract].
18.
Phillippe, M.,
and
A. Basa.
(+)cis-dioxolane stimulation of cytosolic calcium oscillations and phasic contractions of myometrial smooth muscle.
Biochem. Biophys. Res. Commun.
231:
722-725,
1997[Medline].
19.
Phillippe, M.,
and
A. Basa.
Effects of sodium and calcium channel blockade on cytosolic calcium oscillations and phasic contractions of myometrial tissue.
J. Soc. Gynecol. Invest.
4:
72-77,
1997[Medline].
20.
Phillippe, M.,
T. Saunders,
and
A. Basa.
Intracellular mechanisms underlying prostaglandin F2
-stimulated phasic myometrial contractions.
Am. J. Physiol.
273 (Endocrinol. Metab. 36):
E665-E673,
1997[Abstract/Free Full Text].
21.
Ruzycky, A. L.,
and
B. T. Ameredes.
Oxytocin-mediated recruitment of slowly cycling cross bridges and isometric force in rat myometrium.
Am. J. Physiol.
270 (Endocrinol. Metab. 33):
E203-E208,
1996[Abstract/Free Full Text].
22.
Somlyo, A. P.
Rhomantic interludes raise blood pressure.
Nature
389:
908-911,
1997[Medline].
23.
Somlyo, A. P.,
and
A. V. Somlyo.
Signal transduction and regulation in smooth muscle.
Nature
372:
231-236,
1994[Medline].
24.
Szal, S. E.,
J. T. Repke,
E. W. Seely,
S. W. Graves,
C. A. Parker,
and
K. G. Morgan.
[Ca2+]i signaling in pregnant human myometrium.
Am. J. Physiol.
267 (Endocrinol. Metab. 30):
E77-E87,
1994[Abstract/Free Full Text].
25.
Taylor, C. W.,
and
D. Traynor.
Calcium and inositol trisphosphate receptors.
J. Membr. Biol.
145:
109-118,
1995[Medline].
26.
Thornton, S.,
J. Gregory,
and
C. W. Taylor.
The contractile sensitivity of pregnant human myometrium is greater to vasopressin than oxytocin in vitro (Abstract).
J. Obstet. Gynaecol.
18:
S54,
1998.
27.
Thornton, S.,
and
S. K. Smith.
The physiological basis for administration of oxytocin antagonists in preterm labour.
J. Royal. Soc. Med.
88:
166-170,
1995.
28.
Uehata, M.,
T. Ishizaki,
H. Satoh,
T. Ono,
T. Kawahara,
T. Morishita,
H. Tamakawa,
K. Yamagami,
J. Inui,
M. Maekawa,
and
S. Narumiya.
Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension.
Nature
389:
990-994,
1997[Medline].
29.
Word, R. A.
Myosin phosphorylation and the control of myometrial contraction/relaxation.
Semin. Perinatol.
19:
3-14,
1995[Medline].
30.
Wray, S.
Uterine contraction and physiological mechanisms of modulation.
Am. J. Physiol.
264 (Cell Physiol. 33):
C1-C18,
1993[Abstract/Free Full Text].
31.
Yagi, S.,
P. L. Becker,
and
F. S. Fay.
Relationship between force and Ca2+ concentration in smooth muscle as revealed by measurements on single cells.
Proc. Natl. Acad. Sci. USA
85:
4109-4113,
1988[Abstract].
32.
Young, R. C.,
L. Herndon Smith,
and
M. D. McLaren.
T-type and L-type calcium currents in freshly dispersed human uterine smooth muscle cells.
Am. J. Obstet. Gynecol.
169:
785-792,
1993[Medline].
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