This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eisner, D. A. Articles by Trafford, A. W. Search for Related Content PubMed PubMed Citation Articles by Eisner, D. A. Articles by Trafford, A. W. Related Collections Calcium cycling/excitation-contraction coupling

(Circulation Research. 2000;87:1087.)
© 2000 American Heart Association, Inc.

Review

Integrative Analysis of Calcium Cycling in Cardiac Muscle

D. A. Eisner, H. S. Choi, M. E. Díaz, S. C. O’Neill, A. W. Trafford

From the Unit of Cardiac Physiology, University of Manchester, UK.

Correspondence to D.A. Eisner, Unit of Cardiac Physiology, University of Manchester, 1.524 Stopford Bldg, Oxford Rd, Manchester M13 9PT, UK. E-mail Eisner{at}man.ac.uk

	Abstract

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
Abstract—The control of intracellular calcium is central to regulation of contractile force in cardiac muscle. This review illustrates how analysis of the control of calcium requires an integrated approach in which several systems are considered. Thus, the calcium content of the sarcoplasmic reticulum (SR) is a major determinant of the amount of Ca²⁺ released from the SR and the amplitude of the Ca²⁺ transient. The amplitude of the transient, in turn, controls Ca²⁺ fluxes across the sarcolemma and thence SR content. This control of SR content influences the response to maneuvers that modify, for example, the properties of the SR Ca²⁺ release channel or ryanodine receptor. Specifically, modulation of the open probability of the ryanodine receptor produces only transient effects on the Ca²⁺ transient as a result of changes of SR content. These interactions between various Ca²⁺ fluxes are modified by the Ca²⁺ buffering properties of the cell. Finally, we predict that, under some conditions, the above interactions can result in instability (such as alternans) rather than ordered control of contractility.

Key Words: excitation-contraction coupling • sarcoplasmic reticulum • ryanodine receptor

	Introduction

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
Contraction of cardiac muscle is initiated by an increase of [Ca²⁺]_i. The magnitude of this rise of Ca²⁺ or "systolic Ca²⁺ transient" must be controlled to produce a constant cardiac output, must increase to increase the force of contraction of the heart, and may fall in heart failure. The purpose of this article is to discuss the steps responsible for this control. We also point out that focusing attention on any of the individual steps that control Ca²⁺ can be misleading; a full understanding of the control of contraction requires considering how the various steps are integrated.

The reader is referred to recent reviews for general aspects of cardiac excitation-contraction coupling.^{1 2} Much recent work shows that Ca²⁺ is released from the sarcoplasmic reticulum (SR) through a specialized release channel, the ryanodine receptor (RyR), via the process of Ca²⁺-induced Ca²⁺ release (CICR). The entry of a small amount of ("trigger") Ca²⁺ through the sarcolemmal L-type Ca²⁺ current (I_Ca) produces a localized increase of [Ca²⁺]_i in the small space between the surface and SR membranes.^{3 4 5} This then increases the open probability of the RyR, resulting in the efflux of Ca²⁺ from the SR into the cytoplasm. Obviously, for the heart to function as a pump, it must relax as well as contract. Relaxation is initiated by a reduction of [Ca²⁺]_i produced either by pumping back into the SR by the SR Ca²⁺-ATPase (SERCA) or out of the cell, largely by the sarcolemmal Na⁺-Ca²⁺ exchange.

Therefore, each time the heart contracts, Ca²⁺ enters the cytoplasm both from the extracellular fluid and from the SR. For the heart to be in a steady state it is essential that, during each cardiac cycle, exactly that amount of Ca²⁺ that had entered from outside the cell is pumped back out and that which is released by the SR is returned. In the rest of this article, we will show that this requirement for Ca²⁺ flux balance has significant implications for the regulation of contraction. However, before dealing with this regulation, we will address a few comments to the properties of intracellular Ca²⁺ buffers, because these determine the magnitude of the changes of free Ca²⁺ produced by a given Ca²⁺ flux.

	Ca2+ Buffering

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
The magnitude of the systolic rise of [Ca²⁺]_i depends not only on the magnitude of the fluxes but, in addition, on the Ca²⁺ buffering power of the cell. Buffering properties of cardiac cells have been measured in a variety of ways. Relatively direct measurements can be made in permeabilized cells,⁶ but because some cytoplasmic constituents will have been lost, there is a need for data from intact cells. The general approach used is to estimate the change of total Ca²⁺ (Ca_T) by integrating sarcolemmal Ca²⁺ fluxes (under conditions where the SR does not contribute) and compare this with the change of [Ca²⁺]_i ([Ca²⁺]_i) obtained with a fluorescent indicator. One method measures the increase of [Ca²⁺]_i produced by a given I_Ca.⁷ The use of pulses that activate different amounts of I_Ca therefore allows a buffer curve to be produced. An alternative and more rapid method uses caffeine to release Ca²⁺ from the SR, resulting in an increase of [Ca²⁺]_i, which decays as Ca²⁺ is pumped out of the cell on Na⁺-Ca²⁺ exchange. The integral of the Na⁺-Ca²⁺ exchange current (after correction for the electroneutral Ca²⁺-ATPase) gives a measure of the total amount of Ca²⁺ pumped out of the cell, and the change of free Ca²⁺ is obtained from a fluorescent indicator.⁸ One caffeine application then gives an entire curve (see Figure 3B). This method also has the advantage that it provides a quantitative measure of SR content.⁹ To a first approximation, the buffering in the cell can be described with a single K_d, although for more precise work, note should be taken of the fact that the overall buffering is made up of contributions from various components with different K_ds.^{10 11 12} These include troponin and calmodulin as well as membrane binding sites. Values for the overall K_d of 0.5 to 1 µmol/L and for the maximum capacity (B_max) of 100 to 200 µmol/L accessible cell water have been found.^{6 8 11} It is important to remember that the buffering power is not constant but decreases as [Ca²⁺]_i increases. The buffering power at any value of [Ca²⁺]_i can be defined as follows: ß=Ca_T/[Ca²⁺]_i=(K_dxB_max)/K_d+[Ca²⁺]_i)².

View larger version (19K): [in this window] [in a new window]   Figure 3. Figure 3. Quantitative relationships between the various Ca2+ fluxes. A, Dependence of the amplitude of the total (•) and free () Ca2+ transients on SR Ca2+ content. The curves through the data are of the form y=axxn. n=2.1 for the total and 5.2 for the free curves. B, Dependence of free (ordinate) on total (abscissa) Ca2+. C, Dependence of Ca2+ efflux on the amplitude of the Ca2+ transient. D, Dependence of Ca2+ efflux on SR Ca2+ content. n=3.3. All data were obtained from the experiment illustrated in Figure 2 (rat myocyte). Data are modified from Reference 30.

This equation means that ß decreases with increasing [Ca²⁺]_i and therefore that a given increase of total cytoplasmic Ca²⁺ will produce a greater increase of [Ca²⁺]_i as [Ca²⁺]_i increases. For example, with a K_d of 0.6 µmol/L and a B_max of 175 µmol/L accessible cell water, the value of ß changes from 214 at a diastolic [Ca²⁺]_i of 100 nmol/L to 41 at a systolic [Ca²⁺]_i of 1 µmol/L and 16 at 2 µmol/L [Ca²⁺]_i. This [Ca²⁺]_i dependence of buffering power is responsible for the fact that increasing the amplitude of the Ca²⁺ transient increases the rate constant of decay.¹³ Furthermore, as will be described later, it also has important effects on regulation of systolic Ca²⁺.

	Sites at Which CICR May Be Regulated

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
The amount of Ca²⁺ released from the SR for a given entry on I_Ca depends on at least 2 factors, as follows: (1) the properties of the RyR, in particular the relationship between [Ca²⁺]_i and the open probability of the RyR, and (2) the Ca²⁺ content of the SR and thence the Ca²⁺ release flux when a channel opens. In the remainder of this article, we will discuss the contributions of these 2 factors.

	What Regulates SR Ca2+ Content?

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
Much attention has been focused on the effects of directly modulating the activity of SERCA and, in particular, its interaction with the inhibitory accessory protein phospholamban. Phosphorylation of phospholamban relieves the inhibition of SERCA, thereby stimulating its activity.^{14 15} This occurs, for example, during sympathetic stimulation of ß-receptors resulting in an enhanced SR Ca²⁺ content and increased rate of decay of the Ca²⁺ transient.^{16 17} As would be expected, animals deficient in phospholamban (phospholamban knockout mice) have elevated SR Ca²⁺ contents,¹⁸ Ca²⁺ transients with faster rates of decay than controls, and a smaller response to ß stimulation.^{19 20}

Autoregulation of SR Ca²⁺ Content
Another important factor that controls the SR Ca²⁺ content is the level of cytoplasmic Ca²⁺. The higher the [Ca²⁺]_i, the greater the rate of Ca²⁺ pumping into the SR. In addition, Ca²⁺ release from the SR influences sarcolemmal Ca²⁺ fluxes.²¹ This can be seen experimentally if the SR Ca²⁺ content is altered. In the experiment illustrated in Figure 1, the SR had initially been emptied by exposure to 10 mmol/L caffeine. When stimulation was begun, the Ca²⁺ transient was initially very small but then recovered over the next minute as the SR refilled with Ca²⁺ (Figure 1A). Figure 1B shows expanded records of these Ca²⁺ transients. Trace b was recorded in the steady state. Accompanying the large Ca²⁺ transient is Ca²⁺ entry via the L-type Ca²⁺ current and efflux on the Na⁺-Ca²⁺ exchange on repolarization (Figure 1C). It is clear that the entry via the L-type Ca²⁺ current balances the efflux on Na⁺-Ca²⁺ exchange. In other words, in the steady state, Ca²⁺ entry equals efflux. A very different result is seen for the first stimulus (a). The Ca²⁺ entry is larger than in the steady state and the efflux smaller. Therefore, instead of being in Ca²⁺-flux balance, the cell gains Ca²⁺. The Ca²⁺ movements on each pulse are shown in the lower panels of Figure 1A. The larger Ca²⁺ currents when the SR is empty and the decrease in size on refilling result from decreased Ca²⁺-induced inactivation of the L-type Ca²⁺ current.^{22 23 24} The increase of efflux on Na⁺-Ca²⁺ exchange with increased systolic Ca²⁺ simply represents the fact that the rate of Ca²⁺ pumping by Na⁺-Ca²⁺ exchange increases with an increase in the amplitude of the systolic Ca²⁺ transient. The third panel of Figure 1A shows that, on starting stimulation, there is a net gain of Ca²⁺ on each pulse and that this gain disappears in the steady state. Finally, the bottom panel sums the net influx on each pulse. This shows that, by the end of the period shown, the cell had gained 80 µmol/L as a result of stimulation.

View larger version (24K): [in this window] [in a new window]   Figure 1. Figure 1. Relationship between SR Ca2+ content and sarcolemmal Ca2+ fluxes. A, Time course of original data. Top trace shows measurements of [Ca2+]i. The cell was held at -40 mV, and 100-ms-duration depolarizing pulses were applied to 0 mV at 0.5 Hz. Caffeine (10 mmol/L) had been applied until 10 seconds before the record began, to empty the SR. The second panel shows Ca2+ influx (via the L-type Ca2+ current) and efflux on each pulse (measured as shown for specimen records of panel B). The third panel shows net Ca2+ entry (influx-efflux), and the bottom panel, calculated cumulative gain of Ca. B, Specimen records from transients a and b showing (from top to bottom) [Ca2+]i, membrane current, and calculated net sarcolemmal Ca2+ movement. These Ca2+ movements were calculated by integrating the currents after making allowance for the stoichiometry (charges per Ca2+ transported) and allowing for the fact that some of the Ca2+ efflux is produced by the electroneutral sarcolemmal Ca-ATPase. Data were obtained from a ferret myocyte (adapted from Reference 21). C, Expanded tail currents.

This mechanism, which we have previously referred to as "autoregulation,"²⁵ therefore provides a simple way to control the Ca²⁺ content of the SR. An increase of SR Ca²⁺ content will result in greater release, thereby decreasing Ca²⁺ entry into and increasing efflux out of the cell. This will tend to decrease SR content toward the initial level. The effectiveness or "gain" of this system will depend on the relationship between SR Ca²⁺ content and sarcolemmal fluxes. The greater the slope of this relationship, the more tightly controlled will be the SR content. However, as discussed later in this article, there may be reasons for not wanting too steep a relationship.

The above focus on the control of sarcolemmal fluxes by SR content does not mean that control of the SERCA by, for example, phosphorylation of phospholamban is unimportant, but rather that such control mechanisms will simply adjust the set point produced by this autoregulation. It is worthwhile noting that the phospholamban mechanism itself cannot control SR content, as, with the exception of the results of one study,²⁶ phosphorylation depends on parameters other than SR content such as the concentration of cAMP and consequent activation of protein kinase A. In contrast, autoregulation senses the SR content via effects on the amplitude of the systolic Ca²⁺ transient. In this sense, this mechanism carries out a function similar to that of "capacitative" control of Ca²⁺ entry in nonexcitable cells. In capacitative entry, when the endoplasmic reticulum Ca²⁺ content decreases, a signal is produced to increase Ca²⁺ influx across the surface membrane of the cell. This increases Ca²⁺ entry via a channel known as I_CRAC (Ca²⁺ release–activated Ca²⁺ channel). The Ca²⁺ flux through this channel is somehow increased by depletion of the Ca²⁺ content of the endoplasmic reticulum (for review see Barritt²⁷ ). It may be that the large magnitude of the transmembrane Ca²⁺ fluxes in the heart makes modulation of I_Ca and the Na⁺-Ca²⁺ exchange a more suitable strategy than I_CRAC.

Figure 1A shows that increasing the SR Ca²⁺ content (bottom panel) results in a large increase of the amplitude of the systolic Ca²⁺ transient (top). This is emphasized in Figure 3A, which shows that the amount of Ca²⁺ released from the SR increases steeply with increased content such that, at higher contents, a greater fraction of the SR content is released.^{7 21 28 29 30} This steep dependence has 2 consequences, as follows: (1) it makes it imperative that SR content be controlled and (2) it means that an increase of SR Ca²⁺ content is an effective positive inotropic maneuver.

The above considerations mean that, in the steady state, the systolic Ca²⁺ transient must be of a magnitude to produce a Ca²⁺ efflux that exactly balances the Ca²⁺ influx into the cell. This can explain the effects of many inotropic maneuvers without any knowledge of the internal mechanisms of the cell. Thus, an increase of the L-type Ca²⁺ current will increase Ca²⁺ influx. In the steady state, this will require an increased Ca²⁺ transient to support an increased efflux. Catecholamines accelerate the rate of decay of the systolic Ca²⁺ transient.¹⁶ This acceleration will leave less time for the surface membrane to remove calcium, and therefore a larger Ca²⁺ transient is required to support the same Ca²⁺ efflux.

Diastolic Ca²⁺ Fluxes
In the examples presented above, the cell is in calcium balance at the end of systole. It is, however, possible that there may be a net flux of Ca²⁺ during the systolic period that is compensated by an equal and opposite flux during diastole. An example is provided by the effects of cardiac glycosides. These have long been known to increase the magnitude of the systolic Ca²⁺ transient.^{31 32 33} This results from an increase of intracellular Na⁺ concentration and consequent effects on Na⁺-Ca²⁺ exchange leading to an increase of SR Ca²⁺ content.^{34 35} One might expect that this would be due to a decreased ability of Na⁺-Ca²⁺ exchange to remove Ca²⁺ requiring a larger Ca²⁺ transient to produce the same efflux. It appears, however, that the cell loses Ca²⁺ during systole in strophanthidin (as the larger Ca²⁺ transient increases Ca²⁺ efflux and decreases influx) and that this is compensated for by increased diastolic Ca²⁺ entry presumably on Na⁺-Ca²⁺ exchange.³⁶ This emphasizes the potential importance of the diastolic as well as the systolic period. Longer-term³⁷ modulation must also be considered. For example, altering the rate of stimulation can produce gradual changes of contraction that have been linked to changes of intracellular Na⁺ concentration. Such longer-term effects will alter the steady states referred to above by altering SR content.

Limitations on SR Ca²⁺ Content as the Only Regulator of Systolic Ca²⁺
One unanswered question is the extent to which SR Ca²⁺ content can be increased to increase the force of contraction. There is presumably a maximum level of SR Ca²⁺ content. It has been suggested that the maximum SR free Ca²⁺ concentration is limited only by the energy available from ATP.¹² In contrast to this result, agents that inhibit opening of the RyR increase the SR content,³⁸ suggesting that leak of Ca²⁺ out of the SR may limit the maximum content. Furthermore, the maximum content also appears to be limited by spontaneous Ca²⁺ release (waves) occurring at high Ca²⁺ loads.^{39 40} Whatever the origin of the maximum SR content, its existence means that mechanisms in addition to an increase of SR content are required to increase the magnitude of the systolic Ca²⁺ transient.

	Modulation of the RyR

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
It is well established that the open probability of the RyR can be affected by substances other than cytoplasmic Ca²⁺ concentration.⁴¹ Among the substances that increase the open probability are caffeine,⁴² 2,3-butanedione monoxime (BDM),⁴³ and cADP-ribose.^{44 45} The open probability is also increased by phosphorylation.^{46 47 48} Finally, the RyR is also associated with the FK506 binding protein (FKBP12.6). These FK binding proteins stabilize the RyR and, in their absence, long-lasting subconductance states appear, resulting in increased Ca²⁺ flux.⁴⁹ Dissociation of FKBP12.6 from the RyR is increased by immunophilins such as FK506⁵⁰ or phosphorylation.⁴⁸ The open probability can be decreased by local anesthetics such as tetracaine.^{51 52 53} Of potential relevance to ischemia, the open probability is decreased by acidification⁵⁴ or a decrease of cytoplasmic ATP concentration.⁵⁴ For convenience, we will consider this area in 2 parts, modulation of the RyR during systole and diastole.

Systolic Regulation of the RyR
Many previous studies have suggested that maneuvers or circumstances that affect either the level of expression or the open probability of the RyR will alter systolic Ca²⁺. Thus, the depression of contraction in heart failure has been linked to either a decrease in the number of RyRs^{55 56 57 58 59 60 61} or a change in their properties such that fewer are opened by a given trigger increase of [Ca²⁺]_i.^{62 63} This conclusion does not, however, fit well with results examining the effects of maneuvers that alter the RyR pharmacologically. Figure 2Aa shows that increasing the open probability with a low concentration of caffeine produces a purely transient increase in the amplitude of the systolic Ca²⁺ transient.³⁰ Similarly, BDM produces only a transient increase.^{64 65 66} Other work shows that a decrease of open probability of the RyR produced by either tetracaine⁶⁷ or decreased pH⁶⁸ produces a decrease of systolic [Ca²⁺]_i that is also transient.

View larger version (26K): [in this window] [in a new window]   Figure 2. Figure 2. Changes of sarcolemmal fluxes and SR Ca2+ release during potentiation of CICR by caffeine (500 µmol/L). A, Time course. Traces show the following (from top to bottom): a, [Ca2+]i; b, changes in total Ca; c, net sarcolemmal flux calculated as Ca2+ entry on ICa minus efflux on Na+-Ca2+ exchange; d, fractional Ca2+ efflux, fraction of the total Ca2+ transient that is pumped out of the cell; e, SR Ca2+ content; and f, fractional release, fraction of the SR Ca2+ content that is released. B, Specimen records from a control transient (i) and the first in caffeine (ii). For each transient, records show the following (from top to bottom): [Ca2+]i, membrane current, and calculated movement of Ca2+ across the surface membrane. Note that for transient i, influx=efflux, whereas for transient ii, the efflux is greater than the influx. Data are from a rat myocyte; adapted from Reference 30.

The explanation of the transient effects of modulation of the RyR lies with the interactions between SR content and sarcolemmal fluxes reviewed above. This is shown in Figure 2. The application of caffeine produces a transient increase of systolic [Ca²⁺]_i that decays to resting levels. The steady-state Ca²⁺ transient in caffeine is identical to that of the control.³⁰ The specimen traces of Figure 2B show the accompanying membrane currents and calculated Ca²⁺ fluxes for both the control and the first transient in caffeine. In control conditions (Figure 2Bi), Ca²⁺ influx and efflux are equal and the cell is therefore in Ca²⁺ flux balance. However, when caffeine is applied (Figure 2Bii), the increase of the systolic Ca²⁺ transient results in an increase of Ca²⁺ efflux on Na⁺-Ca²⁺ exchange such that the Ca²⁺ efflux is greater than the influx. This results in a predicted loss of Ca²⁺ from the cell. Panel c of Figure 2A shows the net sarcolemmal Ca²⁺ flux (ie, Ca²⁺ entry minus exit). In control conditions, Ca²⁺ entry and exit are balanced. However, the increase in the amplitude of the Ca²⁺ transient in caffeine results in an increase of Ca²⁺ efflux and thence a net loss of Ca²⁺ from the cell and therefore the SR (panel e).

The transient nature of the response to low concentrations of caffeine therefore arises as follows. In the steady state, Ca²⁺ influx equals Ca²⁺ efflux. Initially in caffeine, the larger Ca²⁺ transient results in greater efflux (to a level greater than the influx), resulting in a net loss of Ca²⁺ from the cell and SR. This, in turn, will decrease the amplitude of the Ca²⁺ transient, thereby decreasing the amount of Ca²⁺ pumped out of the cell. Eventually, a new steady state will be reached at which the Ca²⁺ efflux equals the influx. It is important to realize that, so long as neither the Ca²⁺ influx nor the properties of Na⁺-Ca²⁺ exchange are altered, this steady state can only be reached when the Ca²⁺ transient is the same size as the control one.

Direct measurements of SR Ca²⁺ content show that the decrease of the potentiation of systolic Ca²⁺ produced by caffeine or BDM are, indeed, accompanied by a decrease of SR content.^{30 64 66}

The transient decrease of systolic Ca²⁺ produced by agents that decrease the open probability of the RyR has a similar explanation. In brief, the decrease of the Ca²⁺ transient will decrease the amount of Ca²⁺ that leaves the cell (to a value less than that of the influx). This will then result in an increase of SR content^{67 68} and a consequent increase of systolic Ca²⁺ until both systolic Ca²⁺ and Ca²⁺ efflux return to control levels, accompanied by an increase of SR Ca²⁺ content.

If, for example, stimulation of the RyR has no steady-state effect on the amplitude of systolic Ca²⁺ transient, one should consider why it is regulated. There are 2 possible explanations, which can be understood by considering the inotropic effects of increasing the L-type Ca²⁺ current.^{25 30} (1) Maneuvers that increase the amplitude of I_Ca will increase the loading of the cell, and therefore the SR, with Ca²⁺. This will produce a slowly developing increase of systolic Ca²⁺ and cannot produce a physiologically useful rapid increase of contractility. However, the potentiation of the RyR open probability by the increased "trigger" Ca²⁺ entry will result in a transient increase of systolic Ca²⁺. The combination of a slow (but maintained) increase and a transient effect will result in a rapidly developing and maintained increase of systolic Ca²⁺. (2) As pointed out above, excessive increase of SR content results in spontaneous Ca²⁺ release and also an increase of the gradient against which SERCA pumps. Potentiation of RyR open probability will decrease SR Ca²⁺ content and avoid these problems.

Diastolic Modulation of the RyR
In the above analysis, we assumed that the only effect of modulation of the RyR occurs during systole and, therefore, that any efflux of Ca²⁺ from the SR through the RyR during diastole can be ignored. As reviewed above, low concentrations of caffeine produce a purely transient potentiation of SR Ca²⁺ release. In contrast, high concentrations produce a dose-dependent decrease of systolic [Ca²⁺]_i.^{69 70 71} This is because, at these concentrations, caffeine produces a large increase of SR Ca²⁺ permeability, even at rest, and thereby depletes the SR. Even if all of the SR content is released, the amplitude of the Ca²⁺ transient will still be less than in control.

A recent study has suggested that such an increase of diastolic Ca²⁺ release can account for the decrease of Ca²⁺ transient in heart failure.⁴⁸ It was found that the RyR from failing hearts was hyperphosphorylated. This resulted in increased sensitivity to activating Ca²⁺ and the occurrence of subconductance levels. This will increase the Ca²⁺ leak of the SR and thereby decrease its Ca²⁺ content. This is an attractive explanation for decreased contraction that does not suffer from the problems reviewed above for the idea that either the number of RyR or their systolic activation are modified. Nevertheless, flux balance must still be maintained. This might happen in 2 ways. (1) Increased diastolic leak may slow the rate of relaxation of the systolic Ca²⁺ transient. This is the case for high concentrations of caffeine and arises because the increase of leak makes it harder for the SR to remove Ca²⁺ from the cytoplasm. This leads to a decrease in the rate of decay of the residual Ca²⁺ transient. The decay of the Ca²⁺ transient will also be slowed simply as a consequence of the increased Ca²⁺ buffering at lower [Ca²⁺]_i.¹³ Although the Ca²⁺ transient is smaller than is the case under control conditions, the fact that it lasts longer means that the Na⁺-Ca²⁺ exchange has longer to pump Ca²⁺ out of the cell and therefore the efflux can still equal the influx. (2) An alternative explanation is that there may be an increase of diastolic Ca²⁺. This will support an increased Ca²⁺ efflux from the cell during diastole that will compensate for decreased efflux in systole.

	Integration of SR Release, Buffering, and Sarcolemmal Ca2+ Transport

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
The contributions of all of the processes mentioned above can be seen by considering, again, the effects of increasing the open probability of the RyR with caffeine. The data of Figure 2Aa show the transient increase of systolic Ca²⁺ produced by caffeine. The change of cytoplasmic total Ca²⁺ is shown in Figure 2Ab. It is clear that the fractional increase of the amplitude of the free Ca²⁺ transient is larger than that of the total. This (see above) is due to the [Ca²⁺]_i dependence of Ca²⁺ buffering. Figure 2Ac shows the net sarcolemmal Ca²⁺ flux on each pulse. As explained above, this is initially zero as Ca²⁺ influx and efflux are in balance. However, during the onset of the effects of caffeine, there is a net Ca²⁺ efflux. Figure 2Ad shows Ca²⁺ efflux as a fraction of the total Ca²⁺ transient. This is increased but not by as much as the amplitude of the free Ca²⁺ transient (see below). Figure 2Ae shows the calculated SR Ca²⁺ content. This was obtained as follows: sarcolemmal Ca²⁺ flux minus change of total cytoplasmic Ca²⁺. As is emphasized in Figure 2Af, the fraction of SR Ca²⁺ content that is released increases initially in caffeine but then decreases (to a level still higher than that of control) during continued exposure to caffeine. The initial increase is a direct effect of caffeine on the RyR, whereas the subsequent decrease is a consequence of the decrease of SR content. In the steady state, the fraction released is still, however, greater than that of the control, as the same total amount of Ca²⁺ is released from a reduced SR content. This figure therefore shows the complicated consequences of a simple variation of one cellular parameter, the Ca²⁺ sensitivity of the RyR.

The various relationships underlying this behavior are shown in Figure 3. Figure 3A summarizes the dependence of the amplitude of the systolic Ca²⁺ transient on SR Ca²⁺ content. The change of free Ca²⁺ is a much steeper function of SR content than is the total Ca²⁺. The reason for this is shown in Figure 3B; as [Ca²⁺]_i increases, it becomes a very steep function of total Ca²⁺. The Ca²⁺ efflux from the cell is plotted as a function of the amplitude of the free Ca²⁺ transient in Figure 3C. This relationship is tending toward saturation, reflecting the finite K_d of the Na⁺-Ca²⁺ exchange. The graph of Figure 3D shows the dependence of Ca²⁺ efflux on SR content. This therefore involves the following 3 processes: the dependence of the total Ca²⁺ transient on SR content, the buffering properties of the cell, and the dependence of Ca²⁺ efflux on [Ca²⁺]_i. This relationship is less steep than that of [Ca²⁺]_i on SR content because of the flattening effect produced by saturation of Na⁺-Ca²⁺ exchange. The effect of this is visible in Figure 2Ab; the fractional increase of the Ca²⁺ efflux is much less than that of the free Ca²⁺ transient.

In some cases, more than one of the Ca²⁺ regulation processes can be directly affected by a single factor. For example, the activity of both the SR Ca²⁺ ATPase and the RyR are regulated by ATP. During ischemia, therefore, when [ATP] falls, uptake of Ca²⁺ into the SR would be compromised, but inhibition of the RyR might compensate. Some evidence of such effects has been found in intact myocytes from guinea pig hearts in which SR Ca²⁺ content is maintained or rises in metabolic inhibition⁷² and in skinned myocytes from rat hearts in which lowering [ATP] slows reuptake of Ca²⁺ into the SR, while SR Ca²⁺ content is higher than normal.⁷³ It seems likely from these results that lowering [ATP] has more influence on the ability of the SR to store Ca²⁺ through its inhibitory effect on the RyR than through lowering SERCA activity.

	Stability and Alternans

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
The above discussion has described a system whereby an increase of SR Ca²⁺ content leads to an increase of Ca²⁺ efflux and decrease of Ca²⁺ influx that, in turn, compensate for the increased Ca²⁺ content. This autoregulation is a classic negative feedback system. It does, however, involve a delay, as the change of SR Ca²⁺ content on one beat only influences Ca²⁺ fluxes on the next beat. It is well known that delays can cause instability in negative feedback systems. The potential effect of this can be seen qualitatively as follows. Imagine that there is a very steep relationship between SR content and Ca²⁺ efflux. If the cell begins with a large SR content, then the Ca²⁺ transient will result in a large loss of Ca²⁺ from the cell. This will decrease the SR content. The next beat will therefore arise from a depleted SR, resulting in a smaller Ca²⁺ transient and efflux and therefore a net gain of Ca²⁺ by the cell and thence, on the next beat, a large Ca²⁺ transient. If this continues, alternating small and large Ca²⁺ transients will be produced. A simple model of this is shown in Figure 4. Figure 4A shows Ca²⁺ efflux as a function of SR content. This relationship includes the dependence of Ca²⁺ release on SR content, the Ca²⁺ buffering properties of the cytoplasm, and the relationship between [Ca²⁺]_i and Ca²⁺ efflux. For convenience, we represent the overall relationship as follows: efflux=(SR)x(SRⁿ)/K_d+SRⁿ), where the value of n determines the steepness of the curve. Curves are shown for values of n=1, 3, and 6. We assume that the Ca²⁺ influx into the cell per beat is not affected by changes of SR content. This is a simplification of the experimental result (Figure 1). The simulation was begun with an SR content of 100. With n=1, the SR relaxes monotonically to a new level. With n=3, there is a transient oscillation of content before a steady level is reached. However, with n=6, a steady alternans of SR content is produced. Therefore, if the relationship between Ca²⁺ efflux from the cell and SR content is too steep, instability may result. Obviously, if the relationship is shallow, then small changes in influx will result in large changes in SR content. The physiological optimum may therefore be a compromise between these 2 extremes. As shown above (Figure 3), the relationship between SR content and Ca²⁺ efflux from the cell depends on many parameters. It is worth noting that the tendency toward saturation of the Na⁺-Ca²⁺ exchange compensates for that of the Ca²⁺ buffers. It is possible that a linear dependence of Na⁺-Ca²⁺ exchange on [Ca²⁺]_i would result in the sort of instability predicted by Figure 4B.

View larger version (22K): [in this window] [in a new window]   Figure 4. Figure 4. Steep relationship between SR Ca2+ content and efflux may produce alternans. A, Relationship between SR Ca2+ content and Ca2+ efflux. Curves show Ca2+ efflux calculated from the equation efflux=(SR)x(SRn)/(Kd+SRn). The 3 curves correspond to n=1, 3, and 6. Kd is calculated as 50n so that the curves cross at the same point. Horizontal dashed line shows Ca2+ influx per beat and is assumed constant. B, Model predictions. Graphs show SR Ca2+ content as a function of the number of the beat. SR Ca2+ content is initially 100 (off scale at the amplification shown). On each subsequent beat, the cell (and therefore SR) gains 30 via the Ca2+ current and loses an amount of Ca2+ determined by the efflux curves of panel A. From top to bottom, graphs represent values of n=1, 3, and 6. C, Experimental data showing alternans of the amplitude of the Ca2+ transient recorded in a ferret ventricular myocyte.

This alternation of the amplitude of successive Ca²⁺ transients is reminiscent of the phenomenon of mechanical alternans (for review, see Euler⁷⁴ ). An example of an experimentally recorded alternating Ca²⁺ transient is shown in Figure 4C. Of course, other mechanisms may contribute to alternans. For example, it has been suggested that alternans may not involve changes of SR Ca²⁺ content but, rather, of the fraction of Ca²⁺ that is released⁷⁵ (although one would still expect resulting changes of SR content). Nevertheless, an understanding of the factors that normally ensure stability and, in pathological circumstances, allow instability will require taking account of the mechanisms and relationships described in this review.

	Conclusions

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
The work reviewed here makes it clear that the cardiac cell has evolved simple but powerful mechanisms to regulate SR content and sarcolemmal fluxes. Ca²⁺ fluxes produced by one pump or channel affect the concentrations seen by others. This means that, when analyzing even the simplest inotropic interventions, it is important to consider these interactions.

	Acknowledgments

 
Work from this laboratory was supported by The British Heart Foundation and The Wellcome Trust.

Received September 26, 2000; revision received October 20, 2000; accepted October 20, 2000.

	References

Top Abstract Introduction Ca2+ Buffering Sites at Which CICR... What Regulates SR Ca2+... Modulation of the RyR Integration of SR Release,... Stability and Alternans Conclusions References

 
1. Bers DM. Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res. 2000;87:275–281.[Free Full Text]

2. Wier WG, Balke CW. Ca²⁺ release mechanisms, Ca²⁺ sparks, and local control of excitation-contraction coupling in normal heart muscle. Circ Res. 1999;85:770–776.[Free Full Text]

3. Stern MD. Theory of excitation-contraction coupling in cardiac muscle. Biophys J. 1992;63:497–517.[Medline] [Order article via Infotrieve]

4. López-López JR, Shacklock PS, Balke CW, Wier WG. Local calcium transients triggered by single L-type calcium channel currents in cardiac cells. Science. 1995;268:1042–1045.[Abstract/Free Full Text]

5. Cheng H, Lederer WJ, Cannell MB. Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993;262:740–744.[Abstract/Free Full Text]

6. Hove-Madsen L, Bers DM. Passive Ca buffering and SR Ca uptake in permeabilized rabbit ventricular myocytes. Am J Physiol. 1993;264:C677–C686.[Abstract/Free Full Text]

7. Bassani JWM, Yuan W, Bers DM. Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. Am J Physiol. 1995;268:C1313–C1329.[Abstract/Free Full Text]

8. Trafford AW, Díaz ME, Eisner DA. A novel, rapid and reversible method to measure Ca buffering and timecourse of total sarcoplasmic reticulum Ca content in cardiac ventricular myocytes. Pflügers Arch. 1999;437:501–503.

9. Varro A, Negretti N, Hester SB, Eisner DA. An estimate of the calcium content of the sarcoplasmic reticulum in rat ventricular myocytes. Pflügers Arch. 1993;423:158–160.

10. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol. 1983;245:C1–C14.[Abstract/Free Full Text]

11. Berlin JR, Bassani JWM, Bers DM. Intrinsic cytosolic calcium buffering properties of single rat cardiac myocytes. Biophys J. 1994;67:1775–1787.[Medline] [Order article via Infotrieve]

12. Shannon TR, Ginsburg KS, Bers DM. Reverse mode of the sarcoplasmic reticulum calcium-pump and load-dependant cytosolic calcium decline in voltage-clamped cardiac ventricular myocytes. Biophys J. 2000;78:322–333.[Medline] [Order article via Infotrieve]

13. Bers DM, Berlin JR. Kinetics of [Ca²⁺]_i decline in cardiac myocytes depend on peak [Ca²⁺]_i. Am J Physiol. 1995;268:C271–C277.[Abstract/Free Full Text]

14. Hicks MJ, Shigekawa M, Katz AM. Mechanism by which cyclic adenosine 3':5'-monophosphate-dependent protein kinase stimulates calcium transport in cardiac sarcoplasmic reticulum. Circ Res. 1979;44:384–391.[Free Full Text]

15. Tada M, Kirchberger MA, Repke DI, Katz AM. The stimulation of calcium transport in cardiac sarcoplasmic reticulum by adenosine 3':5'-monophosphate-dependent protein kinase. J Biol Chem. 1974;249:6174–6180.[Abstract/Free Full Text]

16. McIvor ME, Orchard CH, Lakatta EG. Dissociation of changes in apparent myofibrillar Ca²⁺ sensitivity and twitch relaxation induced by adrenergic and cholinergic stimulation in isolated ferret cardiac muscle. J Gen Physiol. 1988;92:509–529.[Abstract/Free Full Text]

17. Endoh M, Blinks JR. Actions of sympathomimetic amines on the Ca²⁺ transient and contraction of rabbit myocardium: reciprocal changes in myofibrillar responsiveness to Ca²⁺ mediated through - and ß-adrenoceptors. Circ Res. 1988;62:247–265.[Abstract/Free Full Text]

18. Li L, Chu G, Kranias EG, Bers DM. Cardiac myocyte calcium transport in phospholamban knockout mouse: relaxation and endogenous CaMKII effects. Am J Physiol. 1998;274:H1335–H1347.[Abstract/Free Full Text]

19. Wolska BM, Stojanovic MO, Luo W, Kranias EG, Solaro RJ. Effect of ablation of phospholamban on dynamics of cardiac myocyte contraction and intracellular Ca²⁺. Am J Physiol. 1996;271:C391–C397.[Abstract/Free Full Text]

20. Li L, Desantiago J, Chu G, Kranias EG, Bers DM. Phosphorylation of phospholamban and troponin I in ß-adrenergic-induced acceleration of cardiac relaxation. Am J Physiol. 2000;278:H769–H779.[Abstract/Free Full Text]

21. Trafford AW, Díaz ME, Negretti N, Eisner DA. Enhanced calcium current and decreased calcium efflux restore sarcoplasmic reticulum Ca content following depletion. Circ Res. 1997;81:477–484.[Abstract/Free Full Text]

22. Adachi-Akahane S, Cleemann L, Morad M. Cross-signaling between L-type Ca²⁺ channels and ryanodine receptors in rat ventricular myocytes. J Gen Physiol. 1996;108:435–454.[Abstract/Free Full Text]

23. Grantham CJ, Cannell MB. Ca²⁺ influx during the cardiac action potential in guinea pig ventricular myocytes. Circ Res. 1996;79:194–200.[Abstract/Free Full Text]

24. Sipido KR, Callewaert G, Carmeliet E. Inhibition and rapid recovery of Ca²⁺ current during Ca²⁺ release from sarcoplasmic reticulum in guinea pig ventricular myocytes. Circ Res. 1995;76:102–109.[Abstract/Free Full Text]

25. Eisner DA, Trafford AW, Díaz ME, Overend CL, O’Neill SC. The control of Ca release from the cardiac sarcoplasmic reticulum: regulation versus autoregulation. Cardiovasc Res. 1998;38:589–604.[Abstract/Free Full Text]

26. Bhogal MS, Colyer J. Depletion of Ca²⁺ from the sarcoplasmic reticulum of cardiac muscle prompts phosphorylation of phospholamban to stimulate store refilling. Proc Natl Acad Sci U S A. 1998;95:1484–1489.[Abstract/Free Full Text]

27. Barritt GJ. Receptor-activated Ca²⁺ inflow in animal cells: a variety of pathways tailored to meet different intracellular Ca²⁺ signalling requirements. Biochem J. 1999;337:153–169.

28. Shannon TR, Ginsburg KS, Bers DM. Potentiation of fractional sarcoplasmic reticulum calcium release by total and free intra-sarcoplasmic reticulum calcium concentration. Biophys J. 2000;78:334–343.[Medline] [Order article via Infotrieve]

29. Spencer CI, Berlin JR. Control of sarcoplasmic reticulum calcium release during calcium loading in isolated rat ventricular myocytes. J Physiol (Lond). 1995;488:267–279.[Abstract/Free Full Text]

30. Trafford AW, Díaz ME, Sibbring GC, Eisner DA. Modulation of CICR has no maintained effect on systolic Ca²⁺: simultaneous measurements of sarcoplasmic reticulum and sarcolemmal Ca²⁺ fluxes in rat ventricular myocytes. J Physiol (Lond). 2000;522:259–270.[Abstract/Free Full Text]

31. Allen DG, Blinks JR. Calcium transients in aequorin-injected frog cardiac muscle. Nature. 1978;273:509–513.[Medline] [Order article via Infotrieve]

32. Allen DG, Eisner DA, Lab MJ, Orchard CH. The effects of low sodium solutions on intracellular calcium concentration and tension in ferret ventricular muscle. J Physiol (Lond). 1983;345:391–407.[Abstract/Free Full Text]

33. Wier WG, Hess P. Excitation-contraction coupling in cardiac Purkinje fibers: effects of cardiotonic steroids on the intracellular (Ca²⁺) transient, membrane potential, and contraction. J Gen Physiol. 1984;83:395–415.[Abstract/Free Full Text]

34. Bers DM, Bridge JHB. Effect of acetylstrophanthidin on twitches, microscopic tension fluctuations and cooling contractures in rabbit ventricle. J Physiol (Lond). 1988;404:53–69.[Abstract/Free Full Text]

35. Smith GL, Valdeolmillos M, Eisner DA, Allen DG. Effects of rapid application of caffeine on intracellular calcium concentration in ferret papillary muscles. J Gen Physiol. 1988;92:351–368.[Abstract/Free Full Text]

36. Bennett DL, O’Neill SC, Eisner DA. Strophanthidin-induced gain of Ca²⁺ occurs during diastole and not systole in guinea-pig ventricular myocytes. Pflügers Arch. 1999;437:731–736.

37. Boyett MR, Hart G, Levi AJ, Roberts A. Effects of repetitive activity on developed force and intracellular sodium in isolated sheep and dog Purkinje fibres. J Physiol (Lond). 1987;388:295–322.[Abstract/Free Full Text]

38. Overend CL, Eisner DA, O’Neill SC. The effect of tetracaine on spontaneous Ca release and sarcoplasmic reticulum calcium content in rat ventricular myocytes. J Physiol (Lond). 1997;502:471–479.[Abstract/Free Full Text]

39. Díaz ME, Trafford AW, O’Neill SC, Eisner DA. Measurement of sarcoplasmic reticulum Ca²⁺ content and sarcolemmal Ca²⁺ fluxes in isolated rat ventricular myocytes during spontaneous Ca²⁺ release. J Physiol (Lond). 1997;501:3–16.[Abstract/Free Full Text]

40. Díaz ME, Trafford AW, O’Neill SC, Eisner DA. A measurable reduction of sarcoplasmic reticulum Ca content follows spontaneous Ca release in rat ventricular myocytes. Pflügers Arch. 1997;434:852–854.

41. Meissner G. Ryanodine receptor/Ca²⁺ release channels and their regulation by endogenous effectors. Annu Rev Physiol. 1994;56:485–508.[Medline] [Order article via Infotrieve]

42. Rousseau E, Smith JS, Meissner G. Ryanodine modifies conductance and gating behavior of single Ca²⁺ release channel. Am J Physiol. 1987;253:C364–C368.[Abstract/Free Full Text]

43. Tripathy A, Xu L, Pasek DA, Meissner G. Effects of 2,3-butanedione 2-monoxime on Ca²⁺ release channels (ryanodine receptors) of cardiac and skeletal muscle. J Membr Biol. 1999;169:189–198.[Medline] [Order article via Infotrieve]

44. Sitsapesan R, Williams AJ. Cyclic ADP-ribose, and related compounds activate sheep skeletal sarcoplasmic reticulum Ca²⁺ release channel. Am J Physiol. 1995;268:C1235–C1240.[Abstract/Free Full Text]

45. Sitsapesan R, McGarry SJ, Williams AJ. Cyclic ADP-ribose competes with ATP for the adenine nucleotide sites on the cardiac ryanodine receptor Ca²⁺ release channel. Circ Res. 1994;75:596–600.[Abstract/Free Full Text]

46. Yoshida A, Takahashi M, Imagawa T, Shigekawa M, Takisawa H, Nakamura T. Phosphorylation of ryanodine receptors in rat myocytes during ß-adrenergic stimulation. J Biochem. 1992;111:186–190.[Abstract/Free Full Text]

47. Hohenegger M, Suko J. Phosphorylation of the purified cardiac ryanodine receptor by exogenous and endogenous protein kinases. Biochem J. 1993;296:303–308.

48. Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell. 2000;101:365–376.[Medline] [Order article via Infotrieve]

49. Brillantes A-MB, Ondrias K, Scott A, Kobrinsky E, Ondriasova E, Moschella MC, Jayaraman T, Landers M, Ehrlich BE, Marks AR. Stabilization of calcium release channel (ryanodine receptor) function by FK506-binding protein. Cell. 1994;77:513–523.[Medline] [Order article via Infotrieve]

50. Xiao R-P, Valdivia HH, Bogdanov K, Valdivia C, Lakatta EG, Cheng H. The immunophilin FK506-binding protein modulates Ca²⁺ release channel closure in rat heart. J Physiol (Lond). 1997;500:343–354.[Abstract/Free Full Text]

51. Tinker A, Williams AJ. Charged local anesthetics block ionic conduction in the sheep cardiac sarcoplasmic reticulum calcium release channel. Biophys J. 1993;65:852–864.[Medline] [Order article via Infotrieve]

52. Xu L, Jones R, Meissner G. Effects of local anesthetics on single channel behavior of skeletal muscle release channel. J Gen Physiol. 1993;101:207–233.[Abstract/Free Full Text]

53. Györke S, Lukyanenko V, Györke I. Dual effects of tetracaine on spontaneous calcium release in rat ventricular myocytes. J Physiol (Lond). 1997;500:297–309.[Abstract/Free Full Text]

54. Xu L, Mann G, Meissner G. Regulation of cardiac Ca²⁺ release channel (ryanodine receptor) by Ca²⁺, H⁺, Mg²⁺, and adenine nucleotides under normal and simulated ischemic conditions. Circ Res. 1996;79:1100–1109.[Abstract/Free Full Text]

55. Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M. Alterations in sarcoplasmic reticulum gene expression in human heart failure: a possible mechanism for alterations in systolic and diastolic properties of the failing myocardium. Circ Res. 1993;72:463–469.[Abstract/Free Full Text]

56. Hittinger L, Ghalen B, Chen J, Edwards JG, Kudej RK, Iwase M, Kim S-J, Vatner SF, Vatner DE. Reduced subendocardial ryanodine receptors and consequent effects on cardiac function in conscious dogs with left ventricular hypertrophy. Circ Res. 1999;84:999–1006.[Abstract/Free Full Text]

57. Vatner DE, Sato N, Kiuchi K, Shannon RP, Vatner SF. Decrease in myocardial ryanodine receptors and altered excitation-contraction coupling early in the development of heart failure. Circulation. 1994;90:1423–1430.[Abstract/Free Full Text]

58. Naudin V, Oliviero P, Rannou F, Beuve CS, Charlemagne D. The density of ryanodine receptors decreases with pressure overload-induced rat cardiac hypertrophy. FEBS Lett. 1991;285:1:135–138.[Medline] [Order article via Infotrieve]

59. Kim DH, Mkparu F, Kim CR, Caroll RF. Alteration of Ca²⁺ release channel function in sarcoplasmic reticulum of pressure-overload-induced hypertrophic rat heart. J Mol Cell Cardiol. 1994;26:1505–1512.[Medline] [Order article via Infotrieve]

60. Yamamoto T, Yano M, Kohno M, Hisaoka T, Ono K, Tanigawa T, Saiki Y, Hisamatsu Y, Ohkusa T, Matsuzaki M. Abnormal Ca²⁺ release from cardiac sarcoplasmic reticulum in tachycardia-induced heart failure. Cardiovasc Res. 1999;44:146–155.[Abstract/Free Full Text]

61. Teshima Y, Takahashi N, Saikawa T, Hara M, Yasunaga S, Hidaka S, Sakata T. Diminished expression of sarcoplasmic reticulum Ca²⁺-ATPase and ryanodine sensitive Ca²⁺ channel mRNA in streptozotocin-induced diabetic rat heart. J Mol Cell Cardiol. 2000;32:655–664.[Medline] [Order article via Infotrieve]

62. Gómez AM, Valdivia HH, Cheng H, Lederer MR, Santana LF, Cannell MB, McCune SA, Altschuld RA, Lederer WJ. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science. 1997;276:800–806.[Abstract/Free Full Text]

63. Wessely R, Klingel K, Santana LF, Dalton N, Hongo M, Lederer WJ, Kandolf R, Knowlton KU. Transgenic expression of replication-restricted enteroviral genomes in heart muscle induces defective excitation-contraction coupling and dilated cardiomyopathy. J Clin Invest. 1998;102:1444–1453.[Medline] [Order article via Infotrieve]

64. Trafford AW, Díaz ME, Eisner DA. Stimulation of Ca-induced Ca release only transiently increases the systolic Ca transient: measurements of Ca fluxes and sarcoplasmic reticulum Ca. Cardiovasc Res. 1998;37:710–717.[Abstract/Free Full Text]

65. O’Neill SC, Eisner DA. A mechanism for the effects of caffeine on Ca²⁺ release during diastole and systole in isolated rat ventricular myocytes. J Physiol (Lond). 1990;430:519–536.[Abstract/Free Full Text]

66. Adams WA, Trafford AW, Eisner DA. 2,3-Butanedione monoxime (BDM) decreases sarcoplasmic reticulum Ca content by stimulating Ca release in isolated rat ventricular myocytes. Pflügers Arch. 1998;436:776–781.

67. Overend CL, O’Neill SC, Eisner DA. The effect of tetracaine on stimulated contractions, sarcoplasmic reticulum Ca²⁺ content and membrane current in isolated rat ventricular myocytes. J Physiol (Lond). 1998;507:759–769.[Abstract/Free Full Text]

68. Choi HS, Trafford AW, Orchard CH, Eisner DA. The effect of acidosis on systolic Ca and sarcoplasmic reticulum Ca content in isolated rat ventricular myocytes. J Physiol (Lond). 2000;529:661–668.[Abstract/Free Full Text]

69. Hess P, Wier WG. Excitation-contraction coupling in cardiac Purkinje fibers: effects of caffeine on the intracellular [Ca²⁺] transient, membrane currents, and contraction. J Gen Physiol. 1984;83:417–433.[Abstract/Free Full Text]

70. Konishi M, Kurihara S. Effects of caffeine on intracellular calcium concentrations in frog skeletal muscle fibres. J Physiol (Lond). 1987;383:269–283.[Abstract/Free Full Text]

71. Negretti N, O’Neill SC, Eisner DA. The effects of inhibitors of sarcoplasmic reticulum function on the systolic Ca²⁺ transient in rat ventricular myocytes. J Physiol (Lond). 1993;468:35–52.[Abstract/Free Full Text]

72. Goldhaber JI, Parker JM, Weiss JN. Mechanisms of excitation-contraction coupling failure during metabolic inhibition in guinea-pig ventricular myocytes. J Physiol (Lond). 1991;443:371–386.[Abstract/Free Full Text]

73. Yang Z, Steele DS. Effects of cystolic ATP on spontaneous triggered Ca²⁺-induced Ca²⁺ release in permeabilised rat ventricular myocytes. J Physiol (Lond). 2000;523:29–44.[Abstract/Free Full Text]

74. Euler DE. Cardiac alternans: mechanisms and pathophysiological significance. Cardiovasc Res. 1999;42:583–590.[Free Full Text]

75. Hüser J, Wang YG, Sheehan KA, Cifuentes F, Lipsius SL, Blatter LA. Functional coupling between glycolysis and excitation-contraction coupling underlies alternans in cat heart cells. J Physiol (Lond). 2000;524:795–806.[Abstract/Free Full Text]

This article has been cited by other articles:

				T. L. Domeier, L. A. Blatter, and A. V. Zima Alteration of sarcoplasmic reticulum Ca2+ release termination by ryanodine receptor sensitization and in heart failure J. Physiol., November 1, 2009; 587(21): 5197 - 5209. [Abstract] [Full Text] [PDF]

				Y. Xie, A. Garfinkel, J. N. Weiss, and Z. Qu Cardiac alternans induced by fibroblast-myocyte coupling: mechanistic insights from computational models Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H775 - H784. [Abstract] [Full Text] [PDF]

				C. H. Orchard, M. Pasek, and F. Brette The role of mammalian cardiac t-tubules in excitation-contraction coupling: experimental and computational approaches Exp Physiol, May 1, 2009; 94(5): 509 - 519. [Abstract] [Full Text] [PDF]

				Y. Wu, Z. Gao, B. Chen, O. M. Koval, M. V. Singh, X. Guan, T. J. Hund, W. Kutschke, S. Sarma, I. M. Grumbach, et al. From the Cover: Calmodulin kinase II is required for fight or flight sinoatrial node physiology PNAS, April 7, 2009; 106(14): 5972 - 5977. [Abstract] [Full Text] [PDF]

				Y. Li, M. E. Diaz, D. A. Eisner, and S. O'Neill The effects of membrane potential, SR Ca2+ content and RyR responsiveness on systolic Ca2+ alternans in rat ventricular myocytes J. Physiol., March 15, 2009; 587(6): 1283 - 1292. [Abstract] [Full Text] [PDF]

				T. Tao, S. C. O'Neill, M. E. Diaz, Y. T. Li, D. A. Eisner, and H. Zhang Alternans of cardiac calcium cycling in a cluster of ryanodine receptors: a simulation study Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H598 - H609. [Abstract] [Full Text] [PDF]

				M. E. Mangoni and J. Nargeot Genesis and Regulation of the Heart Automaticity Physiol Rev, July 1, 2008; 88(3): 919 - 982. [Abstract] [Full Text] [PDF]

				S. Ozdemir, V. Bito, P. Holemans, L. Vinet, J.-J. Mercadier, A. Varro, and K. R. Sipido Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca2+ Load Attributable to the Predominance of Forward Mode Block Circ. Res., June 6, 2008; 102(11): 1398 - 1405. [Abstract] [Full Text] [PDF]

				L. J. Wang and E. A. Sobie Mathematical model of the neonatal mouse ventricular action potential Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2565 - H2575. [Abstract] [Full Text] [PDF]

				E. Murphy and C. Steenbergen Ion Transport and Energetics During Cell Death and Protection Physiology, April 1, 2008; 23(2): 115 - 123. [Abstract] [Full Text] [PDF]

				E. Murphy and C. Steenbergen Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury Physiol Rev, April 1, 2008; 88(2): 581 - 609. [Abstract] [Full Text] [PDF]

				C. Orchard and F. Brette t-tubules and sarcoplasmic reticulum function in cardiac ventricular myocytes Cardiovasc Res, January 15, 2008; 77(2): 237 - 244. [Abstract] [Full Text] [PDF]

				C. H. George Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance? Cardiovasc Res, January 15, 2008; 77(2): 302 - 314. [Abstract] [Full Text] [PDF]

				T. Seidler, G. Hasenfuss, and L. S. Maier Targeting Altered Calcium Physiology in the Heart: Translational Approaches to Excitation, Contraction, and Transcription Physiology, October 1, 2007; 22(5): 328 - 334. [Abstract] [Full Text] [PDF]

				M. Seddon, A. M. Shah, and B. Casadei Cardiomyocytes as effectors of nitric oxide signalling Cardiovasc Res, July 15, 2007; 75(2): 315 - 326. [Abstract] [Full Text] [PDF]

				L. M. Livshitz and Y. Rudy Regulation of Ca2+ and electrical alternans in cardiac myocytes: role of CAMKII and repolarizing currents Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2854 - H2866. [Abstract] [Full Text] [PDF]

				C.-C. Chou, S. Zhou, H. Hayashi, M. Nihei, Y.-B. Liu, M.-S. Wen, S.-J. Yeh, M. C. Fishbein, J. N. Weiss, S.-F. Lin, et al. Remodelling of action potential and intracellular calcium cycling dynamics during subacute myocardial infarction promotes ventricular arrhythmias in Langendorff-perfused rabbit hearts J. Physiol., May 1, 2007; 580(3): 895 - 906. [Abstract] [Full Text] [PDF]

				G. M. Kravtsov, K. W. L. Kam, J. Liu, S. Wu, and T. M. Wong Altered Ca2+ handling by ryanodine receptor and Na+-Ca2+ exchange in the heart from ovariectomized rats: role of protein kinase A Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1625 - C1635. [Abstract] [Full Text] [PDF]

				K. Kawai, T. Kawai, J. T. Sambol, D.-Z. Xu, Z. Yuan, F. J. Caputo, C. D. Badami, E. A. Deitch, and A. Yatani Cellular mechanisms of burn-related changes in contractility and its prevention by mesenteric lymph ligation Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2475 - H2484. [Abstract] [Full Text] [PDF]

				D. Noble From the Hodgkin-Huxley axon to the virtual heart J. Physiol., April 1, 2007; 580(1): 15 - 22. [Abstract] [Full Text] [PDF]

				A. Mattiazzi, L. Vittone, and C. Mundina-Weilenmann Ca2+/calmodulin-dependent protein kinase: A key component in the contractile recovery from acidosis Cardiovasc Res, March 1, 2007; 73(4): 648 - 656. [Abstract] [Full Text] [PDF]

				C. Pott, X. Ren, D. X. Tran, M.-J. Yang, S. Henderson, M. C. Jordan, K. P. Roos, A. Garfinkel, K. D. Philipson, and J. I. Goldhaber Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice Am J Physiol Cell Physiol, February 1, 2007; 292(2): C968 - C973. [Abstract] [Full Text] [PDF]

				D. M. Bers Altered Cardiac Myocyte Ca Regulation In Heart Failure. Physiology, December 1, 2006; 21(6): 380 - 387. [Abstract] [Full Text] [PDF]

				E. Picht, J. DeSantiago, L. A. Blatter, and D. M. Bers Cardiac Alternans Do Not Rely on Diastolic Sarcoplasmic Reticulum Calcium Content Fluctuations Circ. Res., September 29, 2006; 99(7): 740 - 748. [Abstract] [Full Text] [PDF]

				G. L. Aistrup, J. E. Kelly, S. Kapur, M. Kowalczyk, I. Sysman-Wolpin, A. H. Kadish, and J. A. Wasserstrom Pacing-induced Heterogeneities in Intracellular Ca2+ Signaling, Cardiac Alternans, and Ventricular Arrhythmias in Intact Rat Heart Circ. Res., September 29, 2006; 99(7): E65 - E73. [Abstract] [Full Text] [PDF]

				D. Sato, Y. Shiferaw, A. Garfinkel, J. N. Weiss, Z. Qu, and A. Karma Spatially Discordant Alternans in Cardiac Tissue: Role of Calcium Cycling Circ. Res., September 1, 2006; 99(5): 520 - 527. [Abstract] [Full Text] [PDF]

				H. Nakayama, B. J. Wilkin, I. Bodi, and J. D. Molkentin Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart FASEB J, August 1, 2006; 20(10): 1660 - 1670. [Abstract] [Full Text] [PDF]

				C. Orchard T-tubule trouble J. Physiol., July 15, 2006; 574(2): 330 - 330. [Full Text] [PDF]

				Y. Shiferaw and A. Karma Turing instability mediated by voltage and calcium diffusion in paced cardiac cells PNAS, April 11, 2006; 103(15): 5670 - 5675. [Abstract] [Full Text] [PDF]

				J. Sun, E. Picht, K. S. Ginsburg, D. M. Bers, C. Steenbergen, and E. Murphy Hypercontractile Female Hearts Exhibit Increased S-Nitrosylation of the L-Type Ca2+ Channel {alpha}1 Subunit and Reduced Ischemia/Reperfusion Injury Circ. Res., February 17, 2006; 98(3): 403 - 411. [Abstract] [Full Text] [PDF]

				L.-Z. Yang, J. Kockskamper, F. R. Heinzel, M. Hauber, S. Walther, J. Spiess, and B. Pieske Urocortin II enhances contractility in rabbit ventricular myocytes via CRF2 receptor-mediated stimulation of protein kinase A Cardiovasc Res, February 1, 2006; 69(2): 402 - 411. [Abstract] [Full Text] [PDF]

				Z. Qu Critical mass hypothesis revisited: role of dynamical wave stability in spontaneous termination of cardiac fibrillation Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H255 - H263. [Abstract] [Full Text] [PDF]

				J. N. Weiss, Z. Qu, P.-S. Chen, S.-F. Lin, H. S. Karagueuzian, H. Hayashi, A. Garfinkel, and A. Karma The Dynamics of Cardiac Fibrillation Circulation, August 23, 2005; 112(8): 1232 - 1240. [Abstract] [Full Text] [PDF]

				D. X. P. Brochet, D. Yang, A. D. Maio, W. J. Lederer, C. Franzini-Armstrong, and H. Cheng Ca2+ blinks: Rapid nanoscopic store calcium signaling PNAS, February 22, 2005; 102(8): 3099 - 3104. [Abstract] [Full Text] [PDF]

				D. A. Eisner, M. E. Diaz, Y. Li, S. C. O'Neill, and A. W. Trafford Stability and instability of regulation of intracellular calcium Exp Physiol, January 1, 2005; 90(1): 3 - 12. [Abstract] [Full Text] [PDF]

				V. Lakireddy, P. Baweja, A. Syed, G. Bub, M. Boutjdir, and N. El-Sherif Contrasting effects of ischemia on the kinetics of membrane voltage and intracellular calcium transient underlie electrical alternans Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H400 - H407. [Abstract] [Full Text] [PDF]

				M. Seth, C. Sumbilla, S. P. Mullen, D. Lewis, M. G. Klein, A. Hussain, J. Soboloff, D. L. Gill, and G. Inesi Sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) gene silencing and remodeling of the Ca2+ signaling mechanism in cardiac myocytes PNAS, November 23, 2004; 101(47): 16683 - 16688. [Abstract] [Full Text] [PDF]

				N. Lowri Thomas, C. H. George, and F. Anthony Lai Functional heterogeneity of ryanodine receptor mutations associated with sudden cardiac death Cardiovasc Res, October 1, 2004; 64(1): 52 - 60. [Abstract] [Full Text] [PDF]

				D. A. Eisner and K. R. Sipido Sodium Calcium Exchange in the Heart: Necessity or Luxury? Circ. Res., September 17, 2004; 95(6): 549 - 551. [Full Text] [PDF]

				S. A. Grandy, E. M. Denovan-Wright, G. R. Ferrier, and S. E. Howlett Overexpression of human {beta}2-adrenergic receptors increases gain of excitation-contraction coupling in mouse ventricular myocytes Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1029 - H1038. [Abstract] [Full Text] [PDF]

				V. E. Bondarenko, G. P. Szigeti, G. C. L. Bett, S.-J. Kim, and R. L. Rasmusson Computer model of action potential of mouse ventricular myocytes Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1378 - H1403. [Abstract] [Full Text] [PDF]

				D. Noble Modeling the Heart Physiology, August 1, 2004; 19(4): 191 - 197. [Abstract] [Full Text] [PDF]

				F. Brette, L. Salle, and C. H. Orchard Differential Modulation of L-type Ca2+ Current by SR Ca2+ Release at the T-Tubules and Surface Membrane of Rat Ventricular Myocytes Circ. Res., July 9, 2004; 95(1): e1 - e7. [Abstract] [Full Text] [PDF]

				Y. Wang and J. I. Goldhaber Return of calcium: Manipulating intracellular calcium to prevent cardiac pathologies PNAS, April 20, 2004; 101(16): 5697 - 5698. [Full Text] [PDF]

				K. S. Ginsburg and D. M. Bers Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca2+ load and Ca2+ current trigger J. Physiol., April 15, 2004; 556(2): 463 - 480. [Abstract] [Full Text] [PDF]

				M. E. Diaz, S. C. O'Neill, and D. A. Eisner Sarcoplasmic Reticulum Calcium Content Fluctuation Is the Key to Cardiac Alternans Circ. Res., March 19, 2004; 94(5): 650 - 656. [Abstract] [Full Text] [PDF]

				P. Tavi, S. Pikkarainen, J. Ronkainen, P. Niemela, M. Ilves, M. Weckstrom, O. Vuolteenaho, J. Bruton, H. Westerblad, and H. Ruskoaho Pacing-induced calcineurin activation controls cardiac Ca2+ signalling and gene expression J. Physiol., January 15, 2004; 554(2): 309 - 320. [Abstract] [Full Text] [PDF]

				B. D. Nearing and R. L. Verrier Tracking cardiac electrical instability by computing interlead heterogeneity of T-wave morphology J Appl Physiol, December 1, 2003; 95(6): 2265 - 2272. [Abstract] [Full Text]

				J. Chen, J. Petranka, K. Yamamura, R. E. London, C. Steenbergen, and E. Murphy Gender differences in sarcoplasmic reticulum calcium loading after isoproterenol Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2657 - H2662. [Abstract] [Full Text] [PDF]

				Y.-k. Ju, W. Huang, L. Jiang, J. A Barden, and D. G Allen ATP modulates intracellular Ca2+ and firing rate through a P2Y1 purinoceptor in cane toad pacemaker cells J. Physiol., November 1, 2003; 552(3): 777 - 787. [Abstract] [Full Text] [PDF]

				H. Takamatsu, T. Nagao, H. Ichijo, and S. Adachi-Akahane L-type Ca2+ channels serve as a sensor of the SR Ca2+ for tuning the efficacy of Ca2+-induced Ca2+ release in rat ventricular myocytes J. Physiol., October 15, 2003; 552(2): 415 - 424. [Abstract] [Full Text] [PDF]

				T. R. Shannon, S. M. Pogwizd, and D. M. Bers Elevated Sarcoplasmic Reticulum Ca2+ Leak in Intact Ventricular Myocytes From Rabbits in Heart Failure Circ. Res., October 3, 2003; 93(7): 592 - 594. [Abstract] [Full Text] [PDF]

				T. Seidler, S. L.W. Miller, C. M. Loughrey, A. Kania, A. Burow, S. Kettlewell, N. Teucher, S. Wagner, H. Kogler, M. B. Meyers, et al. Effects of Adenovirus-Mediated Sorcin Overexpression on Excitation-Contraction Coupling in Isolated Rabbit Cardiomyocytes Circ. Res., July 25, 2003; 93(2): 132 - 139. [Abstract] [Full Text] [PDF]

				S C O'Neill and D A Eisner pH-dependent and -independent effects inhibit Ca2+-induced Ca2+ release during metabolic blockade in rat ventricular myocytes J. Physiol., July 15, 2003; 550(2): 413 - 418. [Abstract] [Full Text] [PDF]

				R. L. Verrier, A. V. Tolat, and M. E. Josephson T-Wave alternans for arrhythmia risk stratification in patients with idiopathic dilated cardiomyopathy J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2225 - 2227. [Full Text] [PDF]

				S. J. Liu, R. H. Kennedy, M. H. Creer, and J. McHowat Alterations in Ca2+ cycling by lysoplasmenylcholine in adult rabbit ventricular myocytes Am J Physiol Cell Physiol, April 1, 2003; 284(4): C826 - C838. [Abstract] [Full Text] [PDF]

				J Guo and H J Duff Inactivation of ICa-L is the major determinant of use-dependent facilitation in rat cardiomyocytes J. Physiol., March 15, 2003; 547(3): 797 - 805. [Abstract] [Full Text] [PDF]

				J. Weisser-Thomas, V. Piacentino III, J. P Gaughan, K. Margulies, and S. R Houser Calcium entry via Na/Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes Cardiovasc Res, March 15, 2003; 57(4): 974 - 985. [Abstract] [Full Text] [PDF]

				L. A Blatter, J. Kockskamper, K. A Sheehan, A. V Zima, J. Huser, and S. L Lipsius Local calcium gradients during excitation-contraction coupling and alternans in atrial myocytes J. Physiol., January 1, 2003; 546(1): 19 - 31. [Abstract] [Full Text] [PDF]

				D.A. Eisner and A.W. Trafford Heart Failure and the Ryanodine Receptor: Does Occam's Razor Rule? Circ. Res., November 29, 2002; 91(11): 979 - 981. [Full Text] [PDF]

				J. Kockskamper and L. A Blatter Subcellular Ca2+ alternans represents a novel mechanism for the generation of arrhythmogenic Ca2+ waves in cat atrial myocytes J. Physiol., November 15, 2002; 545(1): 65 - 79. [Abstract] [Full Text] [PDF]

				M. Nishio, S. W. Ruch, and J. A. Wasserstrom Positive inotropic effects of ouabain in isolated cat ventricular myocytes in sodium-free conditions Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2045 - H2053. [Abstract] [Full Text] [PDF]

				B. D. Nearing and R. L. Verrier Progressive Increases in Complexity of T-Wave Oscillations Herald Ischemia-Induced Ventricular Fibrillation Circ. Res., October 18, 2002; 91(8): 727 - 732. [Abstract] [Full Text] [PDF]

				M.E. Diaz, D.A. Eisner, and S.C. O'Neill Depressed Ryanodine Receptor Activity Increases Variability and Duration of the Systolic Ca2+ Transient in Rat Ventricular Myocytes Circ. Res., October 4, 2002; 91(7): 585 - 593. [Abstract] [Full Text] [PDF]

				L F Santana, E G Chase, V S Votaw, M. T Nelson, and R Greven Functional coupling of calcineurin and protein kinase A in mouse ventricular myocytes J. Physiol., October 1, 2002; 544(1): 57 - 69. [Abstract] [Full Text] [PDF]

				Z. Yang, C. Pascarel, D.S. Steele, K. Komukai, F. Brette, and C.H. Orchard Na+-Ca2+ Exchange Activity Is Localized in the T-Tubules of Rat Ventricular Myocytes Circ. Res., August 23, 2002; 91(4): 315 - 322. [Abstract] [Full Text] [PDF]

				M. E. Young, P. H. Guthrie, P. Razeghi, B. Leighton, S. Abbasi, S. Patil, K. A. Youker, and H. Taegtmeyer Impaired Long-Chain Fatty Acid Oxidation and Contractile Dysfunction in the Obese Zucker Rat Heart Diabetes, August 1, 2002; 51(8): 2587 - 2595. [Abstract] [Full Text] [PDF]

				W. E. Louch, G. R. Ferrier, and S. E. Howlett Changes in excitation-contraction coupling in an isolated ventricular myocyte model of cardiac stunning Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H800 - H810. [Abstract] [Full Text] [PDF]

				K. R Sipido, P. G.A Volders, M. A Vos, and F. Verdonck Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res, March 1, 2002; 53(4): 782 - 805. [Abstract] [Full Text] [PDF]

				Y. Li, E. G. Kranias, G. A. Mignery, and D. M. Bers Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes Circ. Res., February 22, 2002; 90(3): 309 - 316. [Abstract] [Full Text] [PDF]

				V. M. Vizgirda, G. M. Wahler, K. L. Sondgeroth, M. T. Ziolo, and D. W. Schwertz Mechanisms of sex differences in rat cardiac myocyte response to beta -adrenergic stimulation Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H256 - H263. [Abstract] [Full Text] [PDF]

				S. Reiken, M. Gaburjakova, J. Gaburjakova, K.-l. He, A. Prieto, E. Becker, G.-h. Yi, J. Wang, D. Burkhoff, and A. R. Marks {beta}-Adrenergic Receptor Blockers Restore Cardiac Calcium Release Channel (Ryanodine Receptor) Structure and Function in Heart Failure Circulation, December 4, 2001; 104(23): 2843 - 2848. [Abstract] [Full Text] [PDF]

				Y. Li, E. G. Kranias, G. A. Mignery, and D. M. Bers Protein Kinase A Phosphorylation of the Ryanodine Receptor Does Not Affect Calcium Sparks in Mouse Ventricular Myocytes Circ. Res., February 22, 2002; 90(3): 309 - 316. [Abstract] [Full Text] [PDF]

				V. Lukyanenko, I. Gyorke, T. F. Wiesner, and S. Gyorke Potentiation of Ca2+ Release by cADP-Ribose in the Heart Is Mediated by Enhanced SR Ca2+ Uptake Into the Sarcoplasmic Reticulum Circ. Res., September 28, 2001; 89(7): 614 - 622. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eisner, D. A. Articles by Trafford, A. W. Search for Related Content PubMed PubMed Citation Articles by Eisner, D. A. Articles by Trafford, A. W. Related Collections Calcium cycling/excitation-contraction coupling