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Vol. 284, Issue 2, 586-591, February 1998
Departments of
Pharmacology (E.P.) and
Medicine (E.P., L.M., B.S.,
U.T.),
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Abstract |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The effects of ovariectomy and estrogen replacement on myocardial
contractility were examined in female rabbits. Ovariectomy failed to
alter left ventricular mass, papillary muscle cross-sectional area or
isometric force. Estrogen replacement after ovariectomy (0.15 µg/kg/day i.m. 17
-estradiol acetate for 7 days) increased left
ventricular mass and papillary muscle mass, and reduced isometric force
compared to control and ovariectomy groups. Ovariectomy did not alter
increased isometric force with isoproterenol, but decreased the
ED50 for Bay K8644 (compared to control and estrogen groups). Estrogen replacement increased the ED50 for
isoproterenol- and Bay K8644-induced isometric force compared to
control and ovariectomy groups. Ovariectomy increased and estrogen
replacement decreased isometric force associated with increased
Ca++o. Acute exposure to 17-estradiol or
diethylstilbesterol (10
7 M, 106 M) failed
to alter isometric force in control papillary muscles. Estrogen
replacement reduced the number, but not the dissociation constant for
3H-nitrendipine binding in plasma membrane preparations
(compared to ovariectomy and control groups). Peak L-type calcium
currents in isolated ventricular myocytes from the three treatment
groups were not significantly different. The data are consistent with an ovariectomy-induced increase and estrogen-induced decrease in L-type
calcium channel density in rabbit myocardium. Estrogen-induced alterations in L-type calcium channel expression and contractility are
subsequently modified by estrogen-induced cardiac hypertrophy.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Estrogen
therapy in postmenopausal women decreases the risk from coronary
atherosclerosis and coronary artery disease (Bush et al.,
1987
; Guetta and Cannon, 1996). Although many of the beneficial effects
of exogenous estrogen administration may be related to an increase in
serum high density lipoprotein cholesterol and a reduction in serum low
density lipoprotein cholesterol (Bush et al., 1987; Guetta
and Cannon, 1996), estrogen may also have direct actions on the
peripheral vasculature and myocardium. Acute exposure to
17-estradiol increases nitric oxide release from coronary and aortic
vascular endothelium of rabbits at supraphysiologic concentrations
(3.2 × 107 M) and directly relaxes coronary and
aortic vascular smooth muscle at even higher concentrations (3.2 × 106 M) (Ma et al., 1997a). Long-term
17-estradiol administration facilitates nitric oxide release in
retrogradely perfused rabbit hearts (Ma et al., 1997a;
Gorodeski et al., 1995) and facilitates both histamine- and
serotonin-stimulated nitric oxide release (Ma et al.,
1997b), actions consistent with an estrogen-induced increase in
endothelial nitric oxide synthetase (Weiner et al., 1994).
Acute exposure to 17-estradiol has been reported to inhibit calcium
ion entry into both rabbit coronary vascular smooth muscle (Jiang
et al., 1991) and ventricular myocytes from male guinea pigs
(Jiang et al., 1992). Both pharmacologic actions of
17-estradiol lack sensitivity and specificity (Batra, 1990), and are
observed only at supraphysiologic concentrations (
106
M). In vascular smooth muscle, the acute actions of 17-estradiol are
mimicked by the mixed agonist/antagonist, tamoxifen (Song et
al., 1996).
The effects of prolonged estrogen administration have been previously
examined in female rats (Schaible et al., 1984; Scheuer et al., 1987). A modest positive inotropic effect and an
increase in myosin adenosine triphosphatase activity have been
reported, in contrast to the reported negative inotropic actions of
acute estrogen exposure in the isolated rabbit heart (Raddino et
al., 1986; Raddino et al., 1989) and in vascular smooth
muscle (Jiang et al., 1991; Nakajima et al.,
1995). Our studies in female rabbits were performed to provide
pharmacologic mechanisms for altered myocardial contractility observed
with 1) ovariectomy, 2) estrogen replacement therapy and 3) acute
estrogen administration.
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Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Experimental groups.
Experiments were performed in female
rabbits randomly allocated to one of three treatment groups: 1)
control, 2) ovariectomy and 3) ovariectomy + 17-estradiol
acetate (Sigma Chemical Co., St. Louis, MO). Bilateral ovariectomy was
produced in 3 to 4 kg female rabbits anesthetized with 1 to 3%
isoflurane by inhalation (pretreatment with 10 mg/kg ketamine + 5 mg/kg acepromazine i.m.). Beginning 1 wk after ovariectomy, the rabbits
were assigned to ovariectomy (0.1 ml/kg/day sunflower oil for 7 days)
or 17-estradiol acetate (0.15 µg/kg/day 17-estradiol acetate in
0.1 ml/kg/day sunflower oil i.m. for 7 days) treatment groups. The
control group did not undergo ovariectomy, and received no treatment
over the same 14-day period. Food and water was available ad
libitum on a 12-hr light/dark schedule.
Myocardial contractility. Female rabbits from the three treatment groups were anesthetized using inhalational ether. The heart was removed. The base of individual right ventricular papillary muscles and the left atrial appendage were clamped individually to bipolar electrodes. The chordae of papillary muscles and the tip of the left atrial appendage were attached to Grass force transducers by 5-0 suture. The muscle preparations were maintained in a 25-ml tissue baths containing modified Tyrode's solution (140 mM NaCl, 5 mM KCl, 1.0 mM MgCl2, 10 mM glucose, 5 mM HEPES, 1.25 mM CaCl2, 1 mM Na2HPO4, 0.2 mM aspartic acid) at 36°C (pH increased to 7.4 by the addition of 1 M NaOH). Resting tension was adjusted to produce maximal contractile force. Isometric force development was recorded on an oscillographic recorder (Grass model 7B). Rate was controlled by pacing with 4-msec duration square wave stimuli, at twice diastolic threshold.
The rate-isometric force development relationship in papillary muscles was examined at heart rates of 0.5 to 3.0 Hz. Maximal isometric force development was determined during pair-pacing. The dose-response relationship (isometric force) was examined for Bay K8644 (108 M to 106 M in 1/2 log
intervals), isoproterenol (109 M-107 M in
1/2 log increments), and Ca++o (2.5, 3.75 and
5.0 mM) in papillary muscles from each treatment group (stimulated at 1 Hz).
The inotropic actions of acute DES and 17-estradiol
(107 M, 106 M) administration were examined
using papillary muscles from the control treatment group 1) under
baseline conditions, 2) during increased isometric force generation
with Bay K8644 (3.2 × 107 M), 3) during increased
isometric force development with isoproterenol (107 M)
and 4) during increased Ca++o. DES and
17-estradiol were dissolved in 50% ethanol and administered in a
maximal volume of 25 µl ethanol/25 ml Tyrode's solution. Isometric
force was measured 15 min after DES or 17-estradiol administration.
At the conclusion of the experiment, the resting length of the
papillary muscle was measured. The papillary muscle was removed and the
mass was determined gravimetrically. The cross-sectional area was
determined by the following equation: cross-sectional area
(mm2) = mass (mg)/length (mm) × 1.05 (mg/mm3).
Left ventricular mass was also determined gravimetrically for each
treatment group.
Nitrendipine binding.
[3H] Nitrendipine
binding experiments were performed using crude myocardial membranes.
Rabbit hearts were trimmed of excess fat and large vessels, and the
left ventricle (freewall + septum) was minced in 15 volumes of
cold 50 mM Tris-HCl buffer (pH 7.4) using a Brinkman polytron
homogenizer at medium speed (3 × 15 sec with 30-sec interspersed
cooling times in ice). The homogenate was filtered through four layers
of cheesecloth and centrifuged at 43,500 g for 20 min. The
pellet was suspended in 15 ml buffer and re-centrifuged at 43,500 g for 20 min (two times). The final pellet was suspended in
Tris buffer and frozen at 
80°. Protein concentration of the
membrane suspension was determined as described by Lowry et
al. (1951).
-estradiol
(108 M-104 M). Scatchard plots were
created. Binding affinity and relative receptor density were calculated
by least squares linear regression analysis.
Determination of L-type calcium current in isolated ventricular myocytes from female rabbits. Female rabbits from the three treatment groups were administered sodium heparin (100 U) to inhibit blood coagulation and were immediately anesthetized with i.v. sodium pentobarbital (30 mg/kg). The heart was removed and the heart was perfused retrogradely (51 mmHg pressure) with oxygenated buffered saline for 5 min (in mM, NaCl, 145; CaCl2, 1.8; MgCl2, 1.0; NaH2PO4, 1.0; glucose, 11.0; HEPES/NaOH, 10.0) (pH = 7.36) at 36.5°C, followed by perfusion with calcium-free oxygenated buffered saline for 5 min. Perfusion was then initiated with oxygenated buffered saline containing collagenase A (1.0 mg/ml, Boehringer-Mannhein, Indianapolis, IN) and CaCl2 (50 µM) for 30 min. The collagenase solution was washed out for 5 min with oxygenated buffer. The ventricles were removed, minced, washed six times with buffered saline solution and filtered through a nylon mesh with a 200-nm pore size. The myocytes were suspended and stored in Hanks' minimum essential medium (Gibco BRL no. 41600-073, Grand Island, NY) supplemented with (in mM); glucose, 11.0; ribose, 5.0; taurine, 15.0; NaHCO3, 24.0; benzylpenicillin, 100,000 U/liter; and streptomycin, 100 mg/liter (pH = 7.4) (saturated with 95% oxygen:5% carbon dioxide). The myocytes were washed and resuspended in oxygenated, buffered saline 30 min before study in the 2- to 24-hr period after cell separation.
A drop of myocyte suspension was allowed to sediment in a 0.5 ml chamber fixed to the stage of a Nikon TMS-F inverted microscope and superfused at 3.0 ml/min at 37°C. Patch microelectrodes (1.5-2.5 M
) pulled from borosilicate glass capillaries (1.0 mm OD) using a
programmable puller (Sutter Instruments, San Rafael, CA) and polished
using a Narishige microforge were used to establish a 10-15 G
membrane seal. Only rod shaped myocytes with sharp contours, clear
myoplasm and even striations were studied.
Whole cell voltage clamps were performed using an Axopatch 200B,
Digidata 1200 interface and Cyberamp 320 controlled by a Gateway 2000 P5-166 computer and PCLAMP6 software. L-type calcium ion current
(ICa-L) was determined by serially depolarizing the membrane potential (Vm) from a 40 mV holding level in 5 mV increments up to +40 mV for a period of 300 msec. (ICa-L) was
determined in the 5- to 10-min period after seal formation, a period
during which rundown of (ICa-L) is negligible.
(ICa-L) was determined as the difference between the peak
current (2-3 msec after the onset of the depolarization step) and the
current at 290 to 300 msec into the depolarization step. The
composition of the micropipette solution (in mM) was:
potassium-aspartate or KCl, 130; Mg-ATP, 3.0; EGTA, 10; HEPES/KOH, 20 (pH = 7.30). In myocytes from control rabbit hearts,
(ICa-L) was determined before and 10 min after the separate
addition of 106 M or 105 M 17-estradiol
to the perfusate.
Statistics.
Data are expressed as the mean ± S.E.M.
Differences between groups were determined using a one-way analysis of
variance for multiple group or repeated measures as appropriate.
Posttest differences between groups were determined using Neuman-Keuls
or Kruskal-Wallis tests for parametric or nonparametric analysis of
variance analyses as appropriate. P 
.05 was criterion for
significance.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Force generation in right ventricular papillary muscles.
Bilateral ovariectomy failed to alter isometric force development at
contraction rates of 0.25 to 3.0 Hz, compared to the control treatment
group (fig. 1). Long-term administration
of 17-estradiol to ovariectomized rabbits reduced force generation at paced rates of 1.0 to 3.0 Hz (fig. 1). Maximal isometric force elicited by paired pacing was not different for papillary muscles from
the three treatment groups (fig. 2).
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-estradiol administration was cardiotrophic in
ovariectomized rabbits, increasing left ventricular mass and the mass/cross-sectional area of right ventricular papillary muscles (table
1). The negative inotropic actions of
17-estradiol treatment were more prominent when total force was
expressed as force/cross-sectional area (mm2), with maximal
force per cross-sectional area reduced compared to control and
ovariectomy treatment groups (fig. 2).
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-estradiol acetate administration) increased 2-fold
compared to control plasma 17-estradiol concentrations.
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Force generation in right ventricular papillary muscles
effects of
-adrenergic receptor stimulation by isoproterenol and the L-type
calcium ion channel agonist Bay K8644.
Dose-response curves
(isometric force) were performed to both isoproterenol and Bay K8644,
for the three treatment groups. Ovariectomy did not significantly alter
the dose-response relationship from control for isoproterenol (fig.
3), but reduced the ED50 for
Bay K8644 (fig. 4). Subsequent
17-estradiol administration produced a significant shift in the
dose-response relationship to both isoproterenol (fig. 3) and Bay K8644
(fig. 4), increasing the ED50 and reducing the relative
potency of both drugs to increase isometric force.
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Force generation in left atrium and right ventricular papillary
muscleseffects of increased Ca++o.
Under
conditions of "normal" extracellular calcium (2.5 mM) at 2.0 Hz,
isometric contraction was reduced with 17-estradiol treatment in
both right ventricular papillary muscles and left atria (table
3). The differences between groups were
more prominent at increased extracellular calcium ion concentrations
(table 3).
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Acute effects of 17-estradiol and DES upon isometric force in
right ventricular papillary muscles.
17-Estradiol
(107 M, 106 M) and DES (107
M, 106 M) were administered to control rabbit papillary
muscles under 1) control conditions (Ca++o = 2.50 mM), 2) after isoproterenol (107 M) and 3) after Bay
K8644 (3.2 × 107 M) (table
4). The acute administration of both
estrogens failed to significantly alter contraction in control rabbit
papillary muscles.
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Nitrendipine binding.
17-Estradiol treatment decreased the
number, but not the affinity of nitrendipine binding sites in left
ventricular membrane preparations from ovariectomized rabbits (table
5). There were no significant differences
in receptor numbers between control and ovariectomy + estrogen
treatment groups.
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-estradiol
(108 M-104 M). At 104 M,
18% of the specifically-bound 3H-nitrendipine was
displaced. No significant displacement of 3H-nitrendipine
was observed at lower 17-estradiol concentrations.
L-Type calcium current in isolated myocytes from female
rabbits.
Peak L-type calcium current did not differ between the
three treatment groups (table 6). Neither
were there differences in the half-activation and half-inactivation
voltages for L-type currents between the three treatment groups (table
6). Superfusion with oxygenated buffer solution containing
17-estradiol (105 M, but not 106 M) for
15 min reduced peak L-type calcium current by 62 ± 15% without
altering half-activation or half-inactivation voltages. There was
little or no recovery of 17-estradiol induced block with a 10-min
washout using oxygenated buffer solution suggesting time-dependent
rundown of the channel or irreversible blockade. Over the same time
period, rundown of L-type calcium current with oxygenated buffer
solution was 2.5 ± 1.8%/min.
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Acute actions of estrogens upon the heart.
In our studies, the
acute administration of 17-estradiol or DES (107 M,
106 M) failed to alter force development in isolated
papillary muscles from female control rabbits under baseline conditions
or during inotropic stimulation with Bay K8644 (an L-type calcium ion
channel agonist) or isoproterenol (a nonspecific -adrenergic
receptor agonist). Neither did 106 M 17-estradiol
inhibit ICa-L in voltage-clamped ventricular myocytes
despite previous reports demonstrating a significant reduction in
isometric force development in isolated rabbit papillary muscles (Khan
and Wohlfart, 1981) and retrogradely perfused rabbit hearts with
106 M DES or 17-estradiol (Raddino et al.,
1986, 1989). Only 105 M 17-estradiol inhibited
ICa-L in voltage-clamped ventricular myocytes from female
rabbits, an action of 17-estradiol (105 M) previously
reported in ventricular myocytes isolated from male guinea pigs (Jiang
et al., 1992). Although the effects of 17-estradiol on
the kinetics of ICa-L activation, inactivation, and
recovery have not been examined, in neither study (Jiang et al., 1992; present study) was the voltage-dependence of
ICa-L altered by 17-estradiol. Significant direct
cardiovascular actions of acute DES or 17-estradiol administration
have not been reported for drug concentrations less than
106 M.
106 M) of
17-estradiol and other estrogens have direct effects on mammalian
hearts including 1) coronary vasodilation (mediated via direct effects
on vascular smooth muscle (Jiang et al., 1991; Ma et
al., 1997b) and via increased formation of nitric oxide by
vascular endothelium (Bell, 1973; Gisclard et al., 1988; Ma
et al., 1997a, 1997b) and 2) negative inotropy (reduced
ICa-L) (Jiang et al., 1992; present studies). The rapid onset of the pharmacologic effects of supraphysiologic estrogen concentrations (including DES and 17-estradiol) suggests that cytosolic receptor binding, nuclear translocation and
transcription are not essential to mediate the acute negative inotropic
effects of estrogens in the heart and the vasodilatory effects of
estrogens in vascular smooth muscle. Relatively nonspecific membrane
receptors for estrogens have been reported in isolated cell membranes
from human urinary bladder (Batra, 1990) and myometrium (Batra, 1990; Pietras and Szego, 1977). These binding sites may or may not include the L-type calcium ion channels or nitrendipine binding sites. In the
present studies, 17-estradiol (105 M) displaced only
5% of specifically bound nitrendipine from its binding sites while
reducing L-type calcium current by more than 60%. Even the mixed
estrogen agonist/antagonist, tamoxifen, inhibits L-type calcium ion
current in vascular smooth muscle (Song et al., 1996). The
relative nonspecificity of the receptors as well as both binding and
pharmacologic actions of estrogens only at supraphysiologic
concentrations achieved only transiently with administration of large
dose of estrogens fails to suggest an important role for these
processes in the beneficial effects of long-term estrogen
administration on cardiovascular mortality.
Long-term estrogen administration. Multiple and varied effects of long-term estrogen administration are manifested upon the mammalian heart.
1) An increased cardiac mass (Schaible et al., 1984; Scheuer
et al., 1987; present studies).
2) An increase in myosin ATP'ase activity (Scheuer et al.,
1987; Ma et al., 1996) with the formation of cardiac myosin
ATP'ase isoforms not observed in control hearts (Ma et al.,
1996).
3) A restoration of the reduced nitrendipine binding site numbers
observed in rat vas deferens and cardiac membranes after ovariectomy
(Ishii et al., 1988), and a decrease in nitrendipine binding
site numbers in female rabbit hearts (present studies), a musculature
with nitrendipine binding restricted to L-type calcium ion channels
(Lew et al., 1991).
4) A reduction in isometric force generation in isolated papillary
muscles of female rabbits, with no overall decrease in maximal
myocardial force generation per papillary muscle except when maximal
force generation is expressed on the basis of cross-sectional area
(present studies).
5) Antagonism of the positive inotropic actions of Bay K8644 and
isoproterenol in isolated papillary muscles of female rabbits (present
studies).
6) Antagonism of the positive inotropic actions of increased
Ca++o in atrial myocardium and papillary
muscles from female rabbits (present studies).
7) Sustained coronary artery vasodilation and increased nitric oxide
formation (Gorodeski et al., 1995; Ma et al.,
1997a). In an analogous manner, the opposite physiological effects are accentuated in female rabbits undergoing ovariectomy.
The actions of long-term estrogen administration on the cardiovascular
system are multiple and varied. The cellular events may be mediated by
initiating or modifying protein synthesis, and are presumed to be
mediated by the nuclear translocation of cytosolic estrogen receptors
previously documented in vascular smooth muscle (Lin and Shain, 1985;
Lin et al., 1986), vascular endothelium (Colburn and
Buonassisi, 1978) and myocardium (Lin and Shain, 1985; Lin et
al., 1986). The trough plasma 17-estradiol concentrations
present in our studies represent only a 2-fold increase over the normal
physiological range, and remain conspicuously below the
106 M or greater concentrations needed to mediate acute
arterial vasodilation and negative inotropy in myocardium. More
importantly, nuclear translocation of the estrogen receptor (and
physiological actions of estrogens) in the cardiovascular system may be
absent after oophorectomy in female baboons (Lin et al.,
1986).
Long-term estrogen administration produces contradictory actions in the
female rabbit heart. One subset of changes favors increased overall
force development, i.e., increased cardiac mass, increased
papillary muscle cross-sectional area, increased contractile protein
content and increased myosin ATP'ase activity. A second subset of
changes favors decreased overall force generation, i.e., a
decreased number of nitrendipine binding sites/L-type calcium receptors
and a decreased response to positive inotropic agents. The changes may
result in an increased global pump performance (unpublished data), but
decreases the overall efficiency of cardiac muscle performance (based
on cross-sectional area). Similarly, calcium entry into ventricular
myocytes may be impaired through a decreased density of L-type calcium
channels in the membrane, with little overall change in calcium entry
per individual myocyte resulting from an increased sarcolemmal area
(increased cell size/hypertrophy). Both long-term 17-estradiol
administration and ovariectomy failed to alter the voltage-dependence
of ICa-L in addition to failing to alter peak
ICa-L for individual cells of the three treatment groups.
The decreased L-type calcium channel density would also be consistent
with the shift to the right for both isoproterenol and Bay K8644
dose-response curves in the estrogen treatment group.
Pregnancy, a physiologic condition increasing estrogen formation,
increases both the total number of dihydropyridine binding sites and
increases the relative expression of the L-VDCC isoform (Mershon
et al., 1994) in rat myometrium by increasing L-type channel
m-RNA formation. There is thus precedence for altered L-type calcium
channel expression by estrogens in another muscle tissue (myometrium)
as well as in cardiac tissues (Ishii et al., 1988).
Previous studies using papillary muscles from Wistar rats have failed
to demonstrate any decrease in force development associated with
chronic estrogen administration. Cardiac mass, myosin ATP'ase, and
force of contraction are increased (Schaible et al., 1984; Scheuer et al., 1987). No previous determinations of
adrenergic sensitivity or dihydropyridine agonist actions have been
reported for myocardium. Other investigators (Ishii et al.,
1988) have however demonstrated a restoration of decreased nitrendipine
binding site numbers in ovariectomized Wistar rats after chronic
estrogen administration, an action opposite to our findings. However,
less is known about the relationship between the number and function of
nitrendipine binding sites and L-type calcium channels in rat myocardium. Moreover, the role for L-type calcium channels in controlling/altering inotropy in rat myocardium is also less
well-understood.
Clinical implications.
It is uncertain if the long-term
protective effects of estrogen replacement therapy in women involve any
direct effects of estrogens on the heart as described in our studies.
Beneficial effects of long-term estrogen administration have been
described 1) reducing the development of atherosclerosis (Bush et
al., 1987; Guetta and Cannon, 1996) and 2) improving the
vasodilatory potential of normal (Bell, 1973; Jiang et al.,
1991; Ma et al., 1997b) and atherosclerotic (Williams
et al., 1990; Williams et al., 1992) vasculature.
Little is known concerning the net effect of long-term estrogen
administration on the electrical or mechanical consequences of
myocardial ischemia, although the decreased potential for calcium entry
through the L-type channel could provide some beneficial effect during
either global or regional myocardial ischemia (Reimer et
al., 1977; Bush et al., 1981). The potential clinical
consequences of the myocardial changes in women on estrogen replacement
therapy remain uncertain.
| |
Footnotes |
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Accepted for publication October 28, 1997.
Received for publication July 21, 1997.
1 This work was supported by a research grant from the Oklahoma Center for the Advancement of Science and Technology (OCAST).
Send reprint requests to: Dr. Eugene Patterson, Research Service 151-F, DVA Medical Center, 921 NE 13th Street, Oklahoma City, OK 73104.
| |
Abbreviations |
|---|
DES, diethylstilbesterol; CON, control; OVAR, ovariectomy; OVAR + ESTR, ovariectomy + estrogen.
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References |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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-oestradiol on endothelial responses in the rabbit.
J Pharmacol Exp Ther
244:
19-22-oestradiol in vitro.
Br J Pharmacol
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1033-1039[Medline]. affects estrogen receptor distribution and elevates progesterone receptor content in baboon aorta.
Arteriosclerosis
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495-504-estradiol in the rabbit: endothelial-dependent and independent mechanisms of vascular relaxation.
J Cardiovasc Pharmacol
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130-135[Medline]. -estradiol inhibits the voltage-dependent L-type Ca2+ currents in aortic smooth muscle cells.
Eur J Pharmacol
294:
625-635[Medline]. -estradiol on the isolated rabbit heart.
Arch Int Pharmacodyn
281:
57-65.
0022-3565/98/2842-0586$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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J. Wattanapermpool and P. J. Reiser Differential effects of ovariectomy on calcium activation of cardiac and soleus myofilaments Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H467 - H473. [Abstract] [Full Text] [PDF]
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