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1 Division of Cardiology, Department of Medicine, and 2 Department of Molecular Pharmacology and Biological Chemistry and the Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, Illinois 60611
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The inotropic and toxic effects of
cardiac steroids are thought to result from
Na+-K+-ATPase inhibition, with elevated
intracellular Na+(Na
40
mV (to inactivate Na+ current). Similar results were
obtained with both Li+ and NMDG replacement and in the
absence of external K+, indicating that ouabain produced
positive inotropy in the absence of functional Na-Ca exchange and
Na+-K+-ATPase activity. In contrast, ouabain
had no inotropic response in rat ventricular myocytes (10-100
µmol/l). Finally, ouabain reversibly increased Ca2+
overload toxicity by accelerating the rate of spontaneous
aftercontractions (n = 13). These results suggest that
the cellular effects of ouabain on the heart may include actions
independent of Na+-K+-ATPase inhibition, Na-Ca
exchange, and changes in Na
N-methyl-D-glucamine; cardiac glycosides; sarcoplasmic reticulum; digitalis toxicity
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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CARDIAC GLYCOSIDES ARE
WIDELY used clinically to treat congestive heart failure. The
inotropic effect of cardiac steroids is thought to result from
Na+-K+-ATPase inhibition (14,
17). Cardiac steroids cause an increase in intracellular
calcium (Ca
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Electrophysiological and mechanical recordings.
The discontinuous single electrode ("switch") voltage-clamp mode of
the Axoclamp-2 amplifier (Axon Instruments; Foster City, CA) was used
with 2- to 4-M
glass micropipettes filled with pipette solution.
Cell suspension was placed in an experimental chamber mounted on the
stage of an inverted microscope (Nikon Diaphot TMD; Nikon Optical;
Tokyo, Japan). The chamber was perfused (1-2 ml/min) with
Na+-free Tyrode solution heated with a peltier device to
36 ± 1°C. Only rod-shaped, Ca2+-tolerant myocytes
with visible cross-striations were studied. The visual image was
recorded via a video camera attached to the side port of the microscope
and displayed on a video monitor, and the cell image was aligned with
the rasters of a video edge detector (Crescent Electronics; Salt Lake
City, UT). Voltage clamp protocols were directed by pCLAMP6 software
(Axon Instruments). The analog signals from cell shortening,
transmembrane potential, fluo 4-AM fluorescence and current were
digitized at 5 kHz and stored in pCLAMP6 files for later analysis.
70 to 0 mV for 10-20 ms (2 s interpulse
interval). In some experiments, the pulse protocols combined a ramp
from 70 to 40 mV with a step pulse from 40 to 0 mV. L-type
Ca2+ current (ICa) was recorded by a
two-step protocol: a 300-ms step from 70 to 40 mV (to allow
inactivation of INa) was followed by
ICa activation during a 300-ms pulse to 0 mV
(0.2 Hz). Solution exchange in the experimental chamber was completed
within 1 min. In some experiments, myocytes were loaded with 10 µmol/l fluo 4-AM (Molecular Probes) for 30 min at room temperature.
Fluorescence transients are presented relative to resting (diastolic)
fluorescence immediately before depolarization (Ft/F0) with
excitation at 485 nm and emission recorded at 520 nm.
Chemicals and solutions.
Saxitoxin (STX) was purchased from Calbiochem (La Jolla, CA).
Thapsigargin was purchased from Alomone Labs (Jerusalem, Israel). All
other chemicals and pharmacological agents were obtained from Sigma
(St. Louis, MO). Ouabain was dissolved in water stock solution (1 × 10
3 mol/l), which was added directly to the external
solution. Thapsigargin was dissolved in dimethyl sulfoxide stock
solution (1 × 103 mol/l). The sodium-free external
solution consisted of (in mmol/l) 140 LiCl or
N-methyl-D-glucamine (NMDG), 5.4 KCl, 1.5 MgCl2, 5 HEPES, 5.5 glucose, and 0.5 CaCl2; pH
7.4 with Tris base. In some experiments, KCl was omitted from the
solution. Measurements of ICa were made in
external solution containing 0.25 mmol/l BaCl2. The pipette
solution consisted of (in mmol/l) 120 K-aspartate, 25 KCl, 0.5 MgCl2, 4 K2-ATP, 0.06 EGTA, and 20 HEPES; pH
7.2 with KOH at 37°C. EGTA was omitted when cells were loaded with
fluo 4-AM.
Data analysis. Data are presented as means ± SE. Each type of experiment was performed on the number of cells indicated (n) in at least three animals. Data were compared using paired or unpaired Student's t-tests or one-way ANOVA with secondary comparisons made by using a Student-Newman-Keuls test. Differences between sample means were considered significant if P was <0.05, unless indicated otherwise.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of ouabain in Na+-free
conditions.
The first series of experiments investigated the effects of ouabain on
excitation-contraction (E-C) coupling in sodium-free conditions.
Because the goal of these experiments was to examine the effects of
ouabain independent of its actions on
Na+-K+-ATPase inhibition, it was essential to
demonstrate that E-C coupling could be activated during inhibition of
Na+/Ca+ exchange. Therefore, pipette and
external solutions contained no Na+. A low-frequency (0.5 Hz) step pulse to 0 mV for 10-20 ms from a holding potential of
70 mV was used to assess inotropy but without development of
Ca
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Effects of ouabain on
Ca
dF/dt) was
also increased by ouabain application, from 0.035 ± 0.009 U/s in
control to 0.066 ± 0.010 in 3 µmol/l ouabain (n = 12, P < 0.05). There was also a positive inotropic effect coincident with the increase in transient magnitude that was
subsequently abolished by thapsigargin (Fig. 3D). The fact that thapsigargin blocked the rise in Ca
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Effects of ouabain after Na+-channel
block in Na+-free conditions.
Recent reports suggest that open Na+ channels pass
Ca2+ ions in the presence of ouabain, which might
contribute to a positive inotropic effect (33). We
examined the effects of ouabain after Na+ channel block
using two separate protocols. Figure
4A shows the effects of
ouabain after block of Na+ channels with STX application.
Figure 4A, top, shows an inward current before
application of STX, which likely represents Li+ current
through the open Na+ channels. Subsequent superfusion of 5 µmol/l STX eliminated the rapid inward component completely, leaving
only a small component of inward Ca2+ current, which was
unaffected by 3 µmol/l ouabain but was blocked by 20 µmol/l
nifedipine in the maintained presence of STX. Superimposed recordings
in Fig. 4A, bottom, show cell shortening in
control, during superfusion of STX, STX plus ouabain, and during
exposure to nifedipine from the same experiment. Ouabain still induced a positive inotropic effect during STX application in
Na+-free conditions, and all contraction was abolished by
nifedipine.
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70 to
40 mV in the absence of STX (Fig. 4B, top),
only ICa was activated during the test pulse
from 40 to 0 mV. Ouabain had little effect on
ICa despite a modest rundown in magnitude under
these conditions. Fig. 4B, bottom, shows that the
positive inotropic effects of ouabain were retained despite
inactivation of Na+ channels. Subsequent application of
nifedipine completely abolished the inward current and contraction (not
shown). Figure 4C summarizes these results, showing a
positive inotropic effect of ouabain in the presence of STX, which is
abolished by nifedipine and a similar positive inotropic action at
holding potential of 40 mV. These results indicate that
1) the positive inotropic effects of ouabain in
Na+-free conditions do not require functional
Na+ channels, and 2) Ca2+ current
activates contraction both before and during exposure to ouabain under
these experimental conditions.
Because of its critical role in activating contraction, we also
examined the effects of ICa in the positive
inotropic effect of ouabain. The original current recordings and
summarized data in Fig. 5 show that
ouabain (10 µmol/l) had no effect on ICa
activated during depolarization from 40 to 0 mV in
Na+-free conditions (0.25 mol/l BaCl2 present).
Consequently, the positive inotropy is not likely to result from
changes in Ca2+ influx via ICa.
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Positive inotropic effect of ouabain does not require a functional
Na+ pump in
Na+-free conditions.
It is possible that the choice of Li+ as a substitute for
Na+ might still permit continued
Na+/Ca+ exchange during
Na+-K+-ATPase inhibition, thus invoking the
usual Na+ pump lag mechanism for glycoside-induced
inotropy. Thus we examined the effects of ouabain in Na+-
and K+-free external conditions where the exchanger and
Na+-K+-ATPase are inhibited. Figure
6 shows the effects of ouabain in NMDG-replaced, Na+-free Tyrode's solution. Ouabain
produced a positive inotropic effect in NMDG-replaced solution and, as
in the previous experiments, all contraction was abolished by
thapsigargin.
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Effects of ouabain on rat ventricular myocytes.
It is well known that adult rat heart is relatively insensitive to
glycosides compared with "sensitive" species, including guinea pig,
cat, dog, and human (15). Consequently, we investigated the glycoside sensitivity of rat ventricular myocytes in
Na+-free conditions. Figure
8A shows the effects of
ouabain on Ca
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Ouabain reversibly exacerbates
Ca2+-overload toxicity under
Na+-free conditions.
Many cat myocytes demonstrated Ca
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Basis for the inotropic and toxic actions of cardiac glycosides.
The "Na+ pump lag" theory states that cardiac
glycosides bind specifically to and inhibit the sarcolemmal
Na+-K+-ATPase, causing an accumulation of
Na
Alternative actions of cardiac glycosides. One of the possible alternative actions considered in these experiments was that Ca2+ influx via Na+ channels could contribute to inotropic effects of ouabain (33). We found that both pharmacological blockade and voltage-dependent inactivation of INa failed to abolish the inotropic effects of ouabain. In fact, we found that contraction was completely abolished when ICa was blocked by nifedipine. Thus it seems unlikely that slip-mode conductance contributes to inotropic effects of ouabain under our experimental conditions.
We also investigated the possibility that alterations in ICa might contribute to inotropy (16, 19). However, under our conditions, ICa was unchanged despite the development of positive inotropy. In addition, all contractions were abolished by thapsigargin, demonstrating that basal contractions and the positive inotropic stimulation induced by ouabain were the result of normal E-C coupling mechanisms involving Ca2+ influx via L-type Ca2+ channels causing release of Ca2+ from the SR. Thus the effects of ouabain do not appear to include actions on ICa or to alter the normal means of Ca2+ influx. With accumulating evidence that other cellular actions might be involved in digitalis effects in the heart, several reports have suggested the possibility of an intracellular action for glycosides. This is not such an unlikely prospect given the fact that different glycosides (including ouabain) cross the sarcolemma and accumulate in the SR (5). One of the most convincing demonstrations of an intracellular action used pressure injection of ouabain and digoxin into isolated bovine ventricular cells, which resulted in increased contraction, even in the absence of external Na+ and in the presence of extracellular digoxin Fab antibodies, which excluded an action on the Na+-K+-ATPase (11). Nunez-Duran et al. (25) subsequently reported that inhibition of uptake of a glycoside-receptor complex in guinea pig atria prevented inotropic effects of the nonpolar compound ouabain, whereas the normal inotropic response occurred with a lipophilic agent (ouabagenin), suggesting an intracellular action of certain cardiac steroids. One potential locus of intracellular action was suggested by the specific binding of glycosides to SR fractions (5) and increased 45Ca2+ release from cardiac SR by ouabain (9). Little was subsequently published about this interesting possibility until we reported a direct SR action by several glycosides to increase single-channel open probability (Po) of canine crude cardiac SR Ca2+ release channels inserted into artificial lipid bilayers (29). Subsequent reports (22, 23) confirmed that digoxin (1-3 nmol/l) increased Po by increasing the number of openings but did not increase open time except at high drug concentrations (30-100 nmol/l). Thus only 1% or less of the glycoside needs to cross the sarcolemma, which is easily accomplished by lipophillic agents (digoxin) but is also likely to occur with more hydrophilic agents like ouabain with an octanol/water partition coefficient of 0.01 (4). Skeletal channel activity was unaffected by even micromolar concentrations. These authors subsequently reported direct [3H]digoxin binding to SR vesicles, with both high [dissociation constant (Kd) = 10 nmol/l] and low (Kd = 3.5 µmol/l) affinity binding (22). In addition to a contribution to positive inotropy, the agent R-56865 not only blocked digoxin binding to the channel but also abolished arrhythmias in intact hearts, suggesting a toxic consequence of interaction of digoxin with a binding site on the channel. Other possible mechanisms might be involved in the actions of glycosides. Increased sensitivity of the contractile myofilaments might play a role in inotropy, especially because there was a dramatic increase in cell shortening compared with the modest increase in CaSpecies sensitivities of ouabain actions.
One of the characteristics of glycoside actions is the well-known
reduced sensitivity in rat heart compared with most other mammalian
species (15). This difference has been ascribed to the
fact that the glycoside-sensitive 
3-isoform of the
Na+-K+-ATPase is largely replaced by the
insensitive 1-isoform in adult rat heart
(21). We found that rat myocytes were insensitive to
ouabain at concentrations 
100 µmol/l in Na+-free
solutions. This finding suggests that the mechanism responsible for
inotropy in Na+-free solutions is absent in rat heart. We
have recently reported that rat cardiac SR Ca2+ release
channels is activated only at extremely high concentrations of digoxin
(~1 µmol/l) but that dog and human channels are activated at
nanomolar concentrations (32). These observations provide additional evidence that activation of the channel may be involved in
the cellular actions of glycosides in sensitive species (cat, human,
dog, etc.) but does not play a role in the responses of rat heart to glycoside.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-30724.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. A. Wasserstrom, Div. of Cardiology S203, Northwestern Medical School, 303 E. Chicago Ave., Chicago, IL 60611 (E-mail: ja-wasserstrom{at}northwestern.edu).
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. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00203.2002
Received 11 March 2002; accepted in final form 8 July 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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