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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; and 3 Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Prior observations have raised the possibility that
dihydropyridine (DHP) agonists directly affect the sarcoplasmic
reticulum (SR) cardiac Ca2+ release channel [i.e.,
ryanodine receptor (RyR)]. In single-channel recordings of purified
canine cardiac RyR, both DHP agonists (
)-BAY K 8644 and
(+)-SDZ202-791 increased the open probability of the RyR when added to
the cytoplasmic face of the channel. Importantly, the DHP antagonists
nifedipine and ()-SDZ202-791 had no competitive blocking effects
either alone or after channel activation with agonist. Thus there is a
stereospecific effect of SDZ202-791, such that the agonist activates
the channel, whereas the antagonist has little effect on channel
activity. Further experiments showed that DHP agonists changed RyR
activation by suppressing Ca2+-induced inactivation of the
channel. We concluded that DHP agonists can also influence RyR
single-channel activity directly at a unique allosteric site located on
the cytoplasmic face of the channel. Similar results were obtained in
human purified cardiac RyR. An implication of these data is that RyR
activation by DHP agonists is likely to cause a loss of
Ca2+ from the SR and to contribute to the negative
inotropic effects of these agents reported by other investigators. Our
results support this notion that the negative inotropic effects of DHP
agonists result in part from direct alteration in the activity of RyRs.
nifedipine; BAY K 8644; PN-202-791; calcium release channels; sarcoplasmic reticulum
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CERTAIN DIHYDROPYRIDINE (DHP) derivatives, such as (±)- BAY K 8644 (BAYK) and (+)-SDZ202-791, are used widely as specific agonists for the L-type Ca2+ channel located in the surface membrane of many excitable cells, including the heart. Numerous studies (4, 16, 18, 22) demonstrate their ability to increase Ca2+ current (ICa) magnitude, slow inactivation, and produce a positive inotropic action in cardiac tissues. Recent work (6, 12, 13, 17) also suggests that additional actions of BAYK may include an effect on the cardiac sarcoplasmic reticulum (SR) that could influence excitation-contraction coupling independent from its agonistic actions on sarcolemmel Ca2+ channels. These reports found that, aside from its direct positive inotropic effect, BAYK also suppresses SR Ca2+ release and contraction during postrest potentiation, producing a secondary negative inotropic effect. The conclusion from this work was that binding of BAYK to the DHP receptor on the L-type Ca2+ channel had an effect that was somehow translated, through a "functional linkage," to the SR, resulting in a suppression of Ca2+ release (13). Because this action could arise as a consequence of the maintained leak of Ca2+ from the SR, a subsequent study examined the possibility that BAYK might have a direct action to activate the SR Ca2+ release channel or ryanodine receptor (RyR). However, despite an action of BAYK to increase SR Ca2+ leak, as indicated by increased Ca2+ spark frequency, no direct effect on RyR single-channel activity was observed using a crude vesicular SR preparation (17).
The purpose of the present study was to further investigate the possibility of a direct agonist effect on the cardiac RyR. We wanted to test for possible actions of DHP agonists on the RyR in the absence of other regulatory proteins because it is known that the type of RyR preparation used (native vesicles vs. purified channels) may influence the RyR response to a ligand (19). A crude microsome preparation is likely to contain factors in the form of both proteins and other signaling molecules that regulate the RyR. It is possible that, in the process of SR vesicle isolation, these factors may render the vesicular preparation insensitive to activators that might normally be effective under physiological conditions. In addition, it is not yet clear whether these additional regulatory factors operate in SR vesicles, as they would in intact cells, to influence the function and pharmacological sensitivity of RyRs. Thus our single-channel studies were conducted using the purified RyRs, where it is easier to look for direct ligand/receptor interactions.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Single RyR channel studies. Dog cardiac (n = 5) preparations were obtained from animals anesthetized with pentobarbital sodium (35 mg/kg iv) before removal of the heart. Human hearts were obtained from three normal patients who died as a result of illness unrelated to cardiac disease and whose hearts were donated for research purposes because they were unsuitable for transplant. All animal and human tissue use was subject to review and approval by the Internal Animal Care and Use Committee and the Internal Review Board, respectively.
Crude microsomes were obtained from the left ventricle using differential centrifugation. Purification of the canine cardiac SR Ca2+ release channel was performed using 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate solubilization of heavy SR vesicles with subsequent reconstitution of purified protein into proteoliposomes (1, 9, 10, 20). Single-channel recordings were made using the planar lipid bilayer technique with 250 mmol/l KCl and 10 mmol/l HEPES (pH 7.4) on the cis (cytoplasmic) side and trans (luminal) sides of the bilayer. The trans side also contained 1 mmol/l Ca2+, while cis [Ca2+] was measured using a Ca2+-sensitive electrode as being 5 µM. Bilayer composition was 0.4 mg each of phosphatidylserine and phosphatidylethanolamine (Avanti Polar Lipids) suspended in 20 µl of n-decane. Pharmacological agents were added directly to either compartment of the bilayer apparatus after control recordings were obtained, and the experimental protocol was repeated after 1 min of stirring (20). Single-channel data were recorded (Axopatch 200 and 200A amplifiers, Axon Instruments) using pCLAMP version 6.0 software in data files of 30 s in duration at constant holding potentials (Vh) of ±30, ±40, and ±50 mV in most experiments. Data were filtered with an eight-pole Bessel filter (model 902, Frequency Devices) at 2 kHz, digitized at 5 kHz, and analyzed off-line using half-amplitude threshold algorithms. In some experiments, [Ca2+] was altered by addition of admixtures of EGTA and CaCl2 according to Calcium software. Concentrations of Ca2+ were varied over the range of 0.1 µM to 1 mM in this manner. Channel activity was established with free cis [Ca] = 50 µmol/l, and EGTA was then added to reduce [Ca] to 0.1 µmol/l. Data were recorded at40 mV before [Ca] was
increased in a cumulative fashion to 1-1,000 µM to obtain
[Ca2+]-open probability (Po)
curves. Separate experiments were performed in the absence and presence
of 10-30 µM BAYK.
All chemicals were obtained from Sigma with the exceptions of BAYK
(Calbiochem) and (+)- and ()-SDZ202-791, which was a gift from Sandoz Pharmaceutical.
Data analysis. Data are presented as means ± SE. Data were compared using paired or unpaired Student's t-tests or a one-way analysis of variance (with secondary comparisons made using a Student-Newman-Keuls test). Differences between sample means were considered significant if P < 0.05 unless indicated otherwise.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of BAYK on single-channel activity of
purified RyR.
Figure 1A shows recordings
from a single purified dog cardiac Ca2+ release channel
before and during exposure to BAYK (10 µmol/l added to the cis
side). BAYK increased single-channel Po
from 0.38 to 0.80 at a Vh of 40 mV and from
0.19 to 0.78 at a Vh of +40 mV. In eight
experiments, Po increased from 30.9 ± 6.8 to 76.9 ± 4.7 (P < 0.03) in the presence of 10 µM BAYK on the cis side at a Vh of
40 mV. The recording in Fig. 1A, bottom left, shows typical sensitivity of the channel to ryanodine (10 µmol/l), as
demonstrated by the appearance of a stable subconductance state (~60% of the fully open conductance) after addition to the
cis side.
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40 mV), there was a modest increase
in short open lifetimes and a large increase in long opening durations
with a shift to a lower percentage of short openings. Both durations of
closed times were decreased by BAYK, which also induced an
increase in the proportion of shorter closings.
Summarized data include the open lifetime events (in ms;
n = 9) in control as follows: 
1 = 0.90 ± 0.15 and 2 = 2.96 ± 0.41 (where
1, is fast time constant and 2 is slow
time constant), with the percentage of all openings represented by
1 = 65 ± 7%. In the presence of 10 µmol/l BAYK, 1 = 1.88 ± 0.54 (no
significant difference compared with control) and 2 = 7.89 ± 1.69 (n = 9, P < 0.05 compared with control); 1 = 49 ± 7%
(P < 0.05). The increase in Po
was not simply the result of changes in the characteristics of channel
openings; under control conditions, closed lifetime events were
summarized as follows (n = 10): 1 = 1.21 ± 0.17 and 2 = 6.15 ± 0.89;
1 = 50 ± 6%. In the presence of BAYK,
1 = 0.69 ± 0.08 (P < 0.01)
and 2 = 2.65 ± 0.37 (P < 0.001); 1 = 65 ± 4% (P < 0.02). Thus both open and closed events were significantly altered by
BAYK, with a resulting increase in overall Po.
Investigation of the relationship between concentration and
Po (Fig. 1C) demonstrated that the
BAYK concentration at which 50% of the maximal effect was achieved
(EC50) was ~3 µmol/l. These effects of BAYK occurred in
the absence of any change in current magnitude (Fig. 1D) and
in the absence of any obvious voltage dependence (Fig. 1E).
Enantiomeric-specific effects of SDZ202-791 on
single-channel activity.
From the preceding experiments, it was clear that BAYK activated the
cardiac Ca2+ release channel as a result of increasing
longer openings and promoting shorter closings. We also studied the
effects of another DHP agonist, SDZ202-791, whose (+)- and
()-enantiomers allowed the separation of agonist and antagonist
actions, respectively (5, 7, 22). As with BAYK,
addition of the agonist (+)-SDZ202-791 (100 µmol/l) increased
Po from 0.29 to 0.90 (Fig.
2A). Subsequent addition of
the antagonist ()-SDZ202-791 (100 µmol/l) did not affect the
agonist action of the (+)-enantiomer and, in fact, produced a slight
increase in Po. In nine experiments,
Po was 0.13 ± 4.48 in control and
0.58 ± 0.11 in the presence of 100 µmol/l (+)-SDZ202-791
(P < 0.01). Subsequent addition of the antagonist ()-SDZ202-791 caused a small additional increase in
Po, probably reflecting a partial agonist
effect, increasing Po from 0.41 ± 0.16 to
0.58 ± 0.13 (P < 0.03, n = 5)
after addition of ()-SDZ202-791 in the maintained presence of
(+)-SDZ202-791. If there were a competitive interaction between the two
enantiomers at a common receptor site, we would have expected a
reduction in Po under these conditions, which
was not observed. Identical results were obtained with BAYK and
subsequent exposure to nifedipine (up to 100 µmol/l,
n = 4; data not shown).
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)-SDZ202-791 is
precluded by prior occupancy of an allosteric site during exposure to
the (+)-enantiomer. When the order of drug application was reversed
(Fig. 2B), ()-SDZ202-791 had no antagonist action on the
purified cardiac Ca2+ release channel and again induced a
modest activation of the channel. Subsequent addition of (+)-SDZ202-791
then produced the typical agonist effect even after prior exposure to
the ()-enantiomer. This result was confirmed in two additional
experiments. High concentrations of both ()-SDZ202-791 and nifedipine
(100 µmol/l) were responsible for a partial agonist effect,
causing an average increase in Po of
0.21 ± 0.04 when added alone (n = 10 or 5 of each
type, P < 0.001). These results demonstrate that the
response of the cardiac Ca2+ release channel is selective
for specific stereoisomers of the DHP agonists and that there is little
response to traditional antagonists. These observations suggest
that there is a unique Ca2+ channel agonist effect on
the purified cardiac Ca2+ release channel.
Additional experiments were performed to identify the location of the
modulatory site on the channel protein. After addition of
(+)-SDZ202-791 (100 µmol/l) to the trans (luminal) side,
Po was unchanged (Fig. 2C). However,
subsequent addition to the cis side caused the typical
increase in Po from 0.02 to 0.47. Three additional experiments yielded the same results; four experiments with
BAYK also yielded an increase in Po only after
introduction to the cis side. There was little
effect of agonist when applied to the luminal side, and the large
increase in Po occurred only when agonist was
applied to the cytoplasmic side of the channel. These results indicate
that the putative binding site resides on the cytoplasmic face of the channel.
DHP agonists and sensitivity of purified
RyR to Ca2+
concentration.
In an attempt to identify the mechanism by which DHP agonists activate
the Ca2+ release channel, we studied the relationship
between Po and Ca2+ concentration in
the absence and presence of DHP agonists (Fig. 3). Under control conditions, the
purified Ca2+ release channel showed the typical response
to changes in cis [Ca2+]; activation of the
channel occurred when [Ca2+] was increased above 1 µmol/l; maximal activation occurred at a [Ca2+] of
~100 µmol/l. This portion of the relationship reflects the activation of the channel by Ca2+, presumably as a result
of Ca2+ binding to an activation site on the cytoplasmic
side of the channel, whereas the decrease in Po
when [Ca2+] is increased above 300 µmol/l reflects the
binding of Ca2+ to an inactivation site on the channel
(3, 11, 14). When this experiment was performed in the
presence of DHP agonists, Ca2+ dependent activation of
Po was not affected, but there was a dramatic
increase in maximal Po with little indication of
Ca2+-induced inactivation at high [Ca2+].
When the Po-[Ca2+] relationship is
adjusted to maximal Po (Fig. 3,
bottom), there was almost no change in affinity for
Ca2+ (EC50 = 6.8 and 9.6 µmol/l in the
absence and presence of BAYK, respectively). There was also a modest
increase in the Hill coefficient (from 1.45 to 1.98) in the presence of
agonist, suggesting an increase in cooperativity for
Ca2+-induced activation. However, the most striking
implication of these results is the suggestion that Ca2+
channel agonists bring about Ca2+ release channel
activation by suppressing Ca2+-induced inactivation of the
channel.
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Effects of DHP agonists on purified human
RyR.
We also investigated the possibility that the agonist action of DHPs
might occur in the human ventricular Ca2+ release channel
to determine whether the effect is specific to the dog cardiac RyR and
whether this action might have wider implications by its presence in
the human heart. Figure 4 shows the
effects of BAYK (10 µmol/l) on a single purified Ca2+
release channel from a normal human heart. Po
increased from 0.11 to 0.47. Subsequent addition of nifedipine
(100 µmol/l) had no antagonist action on
Po (data not shown), and, in fact, there was a slight increase in activity during exposure to the
antagonist. Summarized results (n = 3) indicated that
Po was 0.23 ± 0.06 in control and
0.74 ± 0.13 in the presence of BAYK. These results demonstrate
that the agonist effect occurs in the human ventricular Ca2+ release channel as well as in the dog.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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DHP agonists and antagonists of L-type Ca2+ channels. It has been known for many years that DHPs act as antagonists to L-type Ca2+ channels. It was subsequently found that some of these agents have optically active stereoisomers that can act as agonists to ICa (7, 16, 22). Thus, in contrast to closely related DHP antagonists, agonists like BAYK increased ICa magnitude and slowed inactivation, causing increased Ca2+ influx with resultant positive inotropy. Single Ca2+ channel recordings in cardiac cells suggested that the changes in whole cell current were the result of BAYK binding to and stabilizing the highly active state of the channel (4). This type of activity is characterized by prolonged open times with a corresponding reduction in the number and duration of closed events (so-called mode 2 activity) compared with normal activity, which is characterized by brief channel openings during depolarization followed by entry into the inactivated state (mode 1). In contrast, the antagonist action is thought to be a result of the ability of DHPs to bind to and stabilize the inactivated state (mode 0) of the Ca2+ channel, where Po is very low.
Sanguinetti et al. (16) subsequently found that there were complex voltage and concentration dependencies to the effects of BAYK; most notably, ICa in cardiac Purkinje fibers was increased by BAYK at negative potentials, whereas an antagonistic action was found at depolarized test potentials. They and others (2) demonstrated that this behavior was the result of preferential binding of the two enantiomers of BAYK under the different experimental conditions; the l- or ()-enantiomer was a
pure agonist, whereas the r- or (+)-enantiomer was an
antagonist. Thus a racemic mixture may give conflicting results
depending on the concentration and voltage dependencies of the two
forms of the drug. Exactly the opposite behavior was observed with
another compound, SDZ202-791, whose (+)-enantiomer was an agonist,
whereas the ()-enantiomer was an antagonist (5, 7, 22).
We found that the effects of the pure agonists on purified SR
Ca2+ release channels were similar to those on
ICa. These agents behaved as if they were
stabilizing the channel in mode 2 or the long opening state,
just as with ICa. Thus channel openings were
prolonged by reduction in closed times with a simultaneous increase in
open times. In striking contrast, the antagonists had no blocking
effects, as if there were no equivalent in the Ca2+ release
channel to drug-induced stabilization of mode 0 for
ICa. In fact, these agents appeared to cause a
modest partial agonist action at the high concentrations used in this
study (30-100 µmol/l), suggesting that the activating receptor
offers at least partial recognition to the opposite (agonist) enantiomer.
Aside from their well-known effects to activate
ICa, our findings have demonstrated a similar
action on the cardiac RyR. Specifically, our observations indicate that
the action of DHP agonists on the cardiac RyR is selective for
activation of a recognition site on the channel. DHP antagonists did
not directly reduce activity nor did they antagonize the increase in
channel activity resulting from prior exposure to agonists. These
results suggest that the antagonists do not occupy a binding site on
the RyR and thus do not affect channel activity directly or displace
previously bound agonist. Even more important is the fact that there is
a clear stereospecificity to the agonist action, which supports the
notion that channel activation is a result of a specific interaction with the RyR and not of nonspecific drug effects.
One of the most intriguing results reported here is that the effect of
DHP agonists may involve a suppression of Ca2+-induced
inactivation. This property of the RyR has been well documented and is
thought to reflect binding of Ca2+ at high concentrations
to a low-affinity site inducing channel closure (3, 14,
17). We found that high-affinity Ca2+-induced
activation of channel activity was nearly unaffected by agonists,
whereas inactivation was largely suppressed. This unusual observation
is among the first to suggest the possibility that pharmacological
activation of the cardiac RyR by certain agents might occur through
selective inhibition of Ca2+-induced inactivation.
Calcium channel agonists and cardiac excitation-contraction coupling. The possibility that the effect of BAYK on excitation-contraction coupling might involve an action on the SR as well as on the L-type Ca2+ channel came from work by Bers and co-workers (6, 12, 13, 17). BAYK produced an increase of Ca2+ influx through ICa but also accelerated the decline of the SR Ca2+ content during rest, thus converting the typical potentiation of contraction after rest to a decay in both the dog and ferret ventricle.
One of the previous studies (13) also found that BAYK enhanced ryanodine binding, suggesting an increase in RyR channel Po. These investigators concluded that the effect of BAYK occurs as a result of a modification of the L-type Ca2+ channel, which is then transmitted via a functional linkage to the SR, causing alterations in SR Ca2+ release. More recently, BAYK was found to increase the frequency of local changes in intracellular [Ca2+] (Ca2+ sparks) without altering their spatial or temporal characteristics (17). This action was strikingly similar to the effects on Ca2+ sparks of low concentrations of ryanodine, which locks the RyR channel in a permanently open state. Virtually all of these results support the idea that BAYK might induce a reduction in SR Ca2+ content, possibly as the result of a ryanodine-like action to promote long-lasting activation of the RyR channels. When this possibility was directly studied in crude SR vesicular Ca2+ release channels isolated from the ferret heart (17), BAYK was found to have no effect on single-channel activity. The authors concluded that BAYK activates SR Ca2+ release at rest but that the effect of BAYK is indirect via an action on the DHP receptor on L-type Ca2+ channels that is transmitted by an unknown mechanism to the SR Ca2+ release channel. In contrast with the results obtained by Satoh et al. (17), our observations suggest that this effect on SR Ca2+ release may be the result of a direct action on the Ca2+ release channel itself and may occur independently of any interactions with sarcolemmal proteins, such as the L-type Ca2+ channel. It is well known that DHPs are very lipophillic, often with a partition coefficient (oil:water) of ~3 (8, 21), so it is highly likely that these agents can easily cross the sarcolemma. The intracellular accumulation of DHPs has in fact been directly demonstrated in ventricular tissue (15). Once in the cytoplasm, they can then gain access to the recognition site on the SR Ca2+ release channel with the resulting functional response of the channel depending on the regulatory factors and mechanisms involved. A direct action of DHP agonists on purified RyRs is consistent with the observations of Satoh et al. (17), who found significant alterations in Ca2+ spark frequency, as would be expected for an agent that increases single RyR channel activity. In addition, a direct effect offers a reasonably straightforward explanation for their findings as well as for the other reported suppressant effects of BAYK on excitation-contraction coupling (6, 12, 13, 17). It is possible that our single-channel data differ from those of Satoh et al. (17) because of differences in experimental conditions. For example, the different response to BAYK of our purified RyRs could arise as a consequence of something as simple as a difference in charge carrier (K+ in the current study compared with Cs+ in Ref. 17). However, there have been few reported differences in pharmacological or physiological sensitivities using different monovalent cationic species (3, 14). A more likely explanation may lie in the possibility that the purification process could alter the pharmacological sensitivity of the RyR. The difference in response to DHP agonists suggests that there are factors associated with the crude channel, possibly but not necessarily proteinaceous in nature, that either preclude access of an agonist to its receptor or regulate the response to the activated receptor in some fashion. We do not yet know which form of the channel more accurately reflects channel behavior under physiological conditions, so it is difficult at this point to determine the role of these regulatory factors in influencing the pharmacological responses of the channel in vivo.| |
ACKNOWLEDGEMENTS |
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We thank Susan Kelly for preparation of figures and data analysis.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-30724 (to J. A. Wasserstrom) and American Heart Association Grant SDG-9730045N (to A. J. Lokuta).
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}nwu.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.
Received 21 April 2000; accepted in final form 4 October 2000.
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TOP
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METHODS
RESULTS
DISCUSSION
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) or presence (
) of 10 µmol/l BAYK where single-channel conductance was 450 and 455 pS,
respectively. Each point represents 3-6 experiments. E:
summary of the relationship between Po and
Vh for 2-8 experiments in the absence
(
and 
, 2 experiments with (+)-202-791 = 30 µmol/l]. Each point indicates
results from 5-12 experiments. Bottom:
Po adjusted to maximal Po
in the absence and presence of BAYK for the Ca2+-induced
activation phase only.
