AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 282: H1047-H1054, 2002. First published October 25, 2001; doi:10.1152/ajpheart.00573.2001
0363-6135/02 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
282/3/H1047    most recent
00573.2001v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Han, C.
Right arrow Articles by Weckström, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Han, C.
Right arrow Articles by Weckström, M.
Vol. 282, Issue 3, H1047-H1054, March 2002

Modulation of action potential by [Ca2+]i in modeled rat atrial and guinea pig ventricular myocytes

Chunlei Han, Pasi Tavi, and Matti Weckström

Division of Biophysics, Department of Physical Sciences, and Department of Physiology, and Biocenter Oulu, University of Oulu, 90014 Oulu, Finland


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

We simulated mechanisms that increase Ca2+ transients with two models: the Luo-Rudy II model for guinea pig (GP) ventricle (GP model) representing long action potential (AP) myocytes and the rat atrial (RA) model exemplifying myocytes with short APs. The interventions were activation of stretch-gated cationic channels, increase of intracellular Na+ concentration ([Na+]i), simulated beta -adrenoceptor stimulation, and Ca2+ accumulation into the sarcoplasmic reticulum (SR). In the RA model, interventions caused an increase of AP duration. In the GP model, AP duration decreased except in the simulated beta -stimulation where it lengthened APs as in the RA model. We conclude that the changes in the APs are significantly contributed by the increase of the Ca2+ transient itself. The AP duration is controlled differently in cardiac myocytes with short and long AP durations. With short APs, an increase of the Ca2+ transient promotes an inward current via Na+/Ca2+-exchanger lengthening the AP. This effect is similar regardless of the mechanism causing the increase of the Ca2+ transient. With long APs the Ca2+ transient increase decreases the AP duration via inactivation of the L-type Ca2+ current. However, L-type current increase (as with beta -stimulation) increases the AP duration despite the simultaneous Ca2+ transient augmentation. The results explain the dispersion of AP changes in myocytes with short and long APs during interventions increasing the Ca2+ transients.

heart; cardiac; calcium; ion channels; contraction


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

THE LENGTH AND SHAPE OF action potentials (APs) of cardiac myocytes are determined by concerted activation and inactivation of depolarizing and repolarizing currents during excitation. Depolarization is controlled primarily by Na+ and Ca2+ currents, whereas repolarization results mostly from activation of several K+ currents (3, 7). During the AP repolarization phase, several currents are also influenced by Ca2+ released from the sarcoplasmic reticulum (SR). Therefore, any stimuli affecting the systolic intracellular Ca2+ concentration ([Ca2+]i) will also influence the AP (19, 38). However, the impact of [Ca2+]i on the AP shape depends on the relative contribution of the Ca2+-dependent currents on the repolarization of the given myocytes. If [Ca2+]i-dependent regulation of the AP depends strongly on the length of the AP, the increase of the Ca2+ transients would result in a different effect on the APs with short or long duration.

In cardiac myocytes Ca2+ transient augmentation can be caused by many mechanisms that are utilized by several hormones and also mechanical stretch of the myocyte. The most powerful stimuli to produce Ca2+ transient augmentation are the activation of beta -adrenoceptors. Activation of these receptors leads to liberation of cAMP and subsequent activation of protein kinase A (PKA), which phosphorylates L-type Ca2+ channels and phospholamban, the protein regulating the SR Ca2+-ATPase, the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA). In addition to direct regulation of Ca2+ handling proteins Ca2+ transient also can be augmented indirectly. The mechanism of endothelin-1 (ET-1) in the cardiac myocytes involves activation of protein kinase C (PKC). The PKC-induced phosphorylation of the Na+/H+ exchanger promotes an increase of the intracellular Na+ concentration ([Na+]i), thereby activating the Na+/Ca2+ exchanger and thus promoting Ca2+ influx and subsequent augmentation of the Ca2+ transients (1). Activation of cation-selective stretch-activated (SA) ion channels would also result in sodium accumulation with similar events that followed.

Because of the interrelationship between APs and intracellular free Ca2+, all mechanisms able to increase Ca2+ transients would have a distinct impact on the shape of APs, and this would conceivably depend on the initial length of the AP. Because the contribution of Ca2+ currents and the Na+/Ca2+ exchanger current (INa/Ca) on the AP repolarization depends on the length of the AP (8, 19, 38), it is possible that activation of the same Ca2+ pathway can produce different AP change in different types of myocytes. To test this hypothesis, we simulated the effect of known mechanisms producing positive inotropy with two mathematical models: the Luo-Rudy II model for guinea pig (GP) ventricles representing long AP myocytes (GP model), and the rat atrial (RA) model as an example of myocytes with short APs (27). When designing the inotropic interventions to be used in the models, one boundary condition was that the effects on the Ca2+ transients should be modest and approximately of the same size, regardless of the type of intervention. This makes it easier to compare the different mechanisms to each other, which facilitates understanding of the regulation of the AP length.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Mathematical Models

The Luo-Rudy II model is a GP model that describes the membrane ionic currents, [Ca2+]i, and sarcoplasmic reticular (SR) function dynamically. It was developed by Luo and Rudy in 1994 (20), and it has been used successfully to simulate the early afterdepolarization (35), delayed afterdepolarization, acute myocardial ischemia (24), the role of ATP-sensitive K+ current (9), and slow changes in response to step change in length (5). The development of this model is mainly based on guinea pig ventricular (GP) myocytes, which have a long AP [the AP duration at the 90% level (APD90) is ~150 ms]. In the present study, this GP model was employed as a representative of species with long APD.

To represent myocytes with short APs (APD90 ~50 ms) we used our previously published RA model (27). The major differences of this model and the GP model are in the potassium currents as detailed previously (27), and all the Ca2+-handling pathways are modeled similarly.

All simulations at 1 Hz were run as long as a steady state of all parameters of the model were reached, normally ~10 min. The effect of any simulated intervention was adjusted in the affected model parameters, on the basis of experimental results, with the increase of the Ca2+ transient amplitude (15-30%). Comparisons were done between the control and the endpoint (steady state) of the simulation with different simulation strategies. All models were created with the use of a Sun workstation running MATLAB version 5.3 (Mathworks).

Simulation Protocols

SA ion channels. The stretch-mediated changes were explored in both the RA and GP models by implementing SA conductance, and the ensuing current (Istretch) into the model cell membrane. The properties of this conductance were based on the features of the SA channels in the experimental findings from isolated rat ventricular myocytes (36). Istretch is a nonselective cationic current, carrying Na+ and K+ ions with a reversal potential of -6 mV (37) with the following formalism
I<SUB>stretch</SUB><IT>=</IT>−<IT>&ggr;</IT><SUB>Na</SUB>(8.3<IT>−</IT>5SL)(<IT>E</IT><SUB>m</SUB><IT>−E</IT><SUB>Na</SUB>)<IT>−&ggr;</IT><SUB>K</SUB>(8.3<IT>−</IT>5SL)(<IT>E</IT><SUB>m</SUB><IT>−E</IT><SUB>K</SUB>)
where gamma  = maximal conductance, gamma Na = 0.9 nS, gamma K = 1.17 nS, SL is sarcomere length, Em is membrane potential, ENa is sodium reversal potential, and EK is potassium reversal potential. The SL of 1.75 µm is set as a resting length of sarcomere. In stretch simulation, the length of sarcomere is increased 3.2%, i.e., to equivalent of 1.8 µm (see also Ref. 27).

Simulation of the ET-1-induced Ca2+ transient augmentation. During ET-1 stimulation [Na+]i increases because of the activation of the Na+/H+ exchanger via PKC phosphorylation. This leads to a secondary increase in the [Ca2+]i transients (1). Because Na+ accumulation into the cytosol is the change that promotes Ca2+ accumulation, we simulated the ET-1 effect by increasing [Na+]i from 10 to 14 mmol/l in both models.

Ca2+ accumulation by PKA phosphorylation. The increase of Ca2+ transients during beta -adrenoceptor stimulation results from the PKA-induced phosphorylation of L-type Ca2+ channels and the phospholamban. The L-type channel phosphorylation increases the peak Ca2+ current during excitation. The mechanism of this may be the shift of the current-voltage relation towards more negative potentials (14), resulting in larger Ca2+ current during APs. The simultaneous phospholamban phosphorylation increases Ca2+ storage into the SR stores via increased activity of SERCA, leading to augmented Ca2+ release during Ca2+-induced Ca2+ release. To simulate modest increase of the Ca2+ transients during beta -stimulation the maximum conductance of the L-type Ca2+ channel was increased by 1.5, and the the SERCA activity was increased by 1.5. In strong beta -stimulation, the changes in the Ca2+ transients are much bigger (see Ref. 3 for a review) but in this study this minor change was used to facilitate comparison with the results of other inotropic interventions in the model.

SR Ca2+ content. To simulate the SR Ca2+ loading, we had to take into account the different contribution of the SR Ca2+ release in the two different types of myocytes. In the guinea pig ventricle, the contribution of the SR Ca2+ release on the Ca2+ transient is ~60-70%, and this ratio is much greater, up to 93%, in the rat atrium (4). To produce an equal change in the Ca2+ transient in both models we increased the SR Ca2+ content by 20% in the RA model and by 50% in the GP model. Again, this does not necessarily reflect the true relationship of the effects of SR loading in the two cell types but produced changes in the Ca2+ transients that could easily be compared with other interventions.

Simulated clamping of ICa,L or INa/Ca. For exploring the different contributions of the L-type Ca+ current (ICa,L) and the INa/Ca on the APD in response to elevation of [Ca2+]i, we used simulations with "clamped" L-type currents and INa/Ca. That means that under conditions of increased Ca2+ transients, induced by increased SR Ca2+ content, the time-course of the Ca2+ transient was clamped to the value during the intervention, and either ICa,L or INa/Ca was forced ("clamped") to the value in control condition. All other variables were allowed to change freely. In this way, it was possible to isolate directly the contribution of ICa,L or INa/Ca to the change of APD.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The simulations presented in this study investigate the effects of Ca2+ transient augmentation on the AP waveform of the cardiac myocytes. By employing two mathematical models of cardiac myocytes with different electrophysiological characteristics, we examined the potential mechanisms causing the diversity of changes of APDs induced by different strategies of Ca2+-induced inotropy in short and long AP species. Simulations included the following: 1) activation of SA-channel current (Istretch), 2) elevation of the [Na+]i to promote Ca2+ influx through reverse mode of the Na+/Ca2+ exchanger (Na<UP><SUB>i</SUB><SUP>+</SUP></UP>), 3) increase of the ICa,L during and increased activity of SERCA, and 4) increased Ca2+ accumulation into the SR. The main results from the present study are summarized in numerical form in Table 1, where parameters for AP configuration (APD30 and APD90), the main Ca2+-modulated membrane currents (the peaks of ICa,L and INa/Ca), and two main intracellular ion concentrations ([Ca2+]i and [Na2+]i) are given in all simulation protocols in RA and GP model cells.

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Results for important indexes of APs, ICa,L, INa/Ca, and intracellular sodium under control and different stimulation conditions

Activation of SA Ion Channels

Figure 1 shows the effect of the activation of a nonselective SA conductance in RA and GP models. The peak [Ca2+]i transient was increased to 1.48 µM from 1.02 µM in RA model (Fig. 1A) and to 1.33 µM from 1.16 µM in GP model cell (Fig. 1B). The duration of the AP is prolonged in RA model cell and decreased in GP model. APD90 increased from 52 ms to 61 ms in RA model, and decreased from 144 to 129 ms in the GP model, respectively. Because the reversal potential of the SA current (ISAC) was -6 mV in the model, it will generate an inward (depolarizing) current at voltage values below this value of membrane voltage. However, at more positive potentials ISAC is outward, and will accelerate the early repolarization in both model APs. This effect is small in the RA model but more prominent in the GP model. The other contributing factor to the change in APs is the increased Ca2+ release. Because the SA current is mainly carried by Na+ ions, the activation of the current promotes Na+ accumulation, which is compensated by the changes in the INa/Ca. SA channel current therefore causes increased Ca2+ accumulation and its increased storage into the SR, leading to augmented Ca2+ release during excitation. In the GP model, the increased Ca2+ transient causes more prominent Ca2+-dependent inactivation of the ICa,L, which as such shortens the AP duration. The peak of the ICa,L is slightly larger because of the small decrease in voltage-dependent inactivation due to the small decrease in the peak depolarization of the AP. In the RA model, the AP is so short that the Ca2+-dependent inactivation contributes very little to the AP waveform. In both models, bigger Ca2+ transients modulate the current via Na+/Ca2+ exchange. In the RA model this current has a depolarizing effect at negative potentials (an inward current) and increases the AP duration. In the GP model the INa/Ca is outward up to 100 ms after the onset of the AP. Thus NaCa exchange produces a repolarizing current shortening the AP in the GP model cell. This effect is influenced by the fact that ISAC activation produces a Na+ accumulation. At diastolic membrane potential the [Na+]i increased from 10.9 to 11.5 mM in the RA model, and from 10.2 to 13.1 mM in the GP model. However, the change of the NaCa exchanger reversal potential on [Na+]i increase is small compared with the increase of the Ca2+ transient.


View larger version (19K):
[in this window]
[in a new window]
  		Fig. 1.   Effects of the stretch-activated (SA) current (ISAC) on model cells. Comparison of steady-state responses before (solid line) and after (dashed line) stretch. A: rat atrial (RA) model; B: Luo-Rudy model [guinea pig (GP) model]. Top to bottom, action potential (AP), Ca2+ transient ([Ca2+]i), L-type calcium current (ICa,L) and the Na+/Ca2+ exchanger current (INa/Ca).

Role of sodium accumulation

To simulate sodium accumulation by PKC-dependent Na+/H+-exchanger activation we increased the diastolic [Na+]i from 10.9 to 14 mM in the RA model and from 10.2 to 14 mM in the GP model, an intervention that produced an increase of the Ca2+ transients (Fig. 2). Similarly, as during SA channel activation in the GP model, APD90 is reduced from 143 to 114 ms because of the increased inactivation of the ICa,L and increased outward INa/Ca, both caused by the augmented Ca transients. The duration of the AP in the RA model cell shows only minor changes on increased [Ca2+]i. The APD90 increases from 50 to 55 ms. This is contributed by the elevation of [Na+]i, which reduces inward INa/Ca of the Ca+ transient triggered by shifting the reversal potential of the exchanger to more positive potentials.


View larger version (17K):
[in this window]
[in a new window]
  		Fig. 2.   Effect of increased intracellular Na+ concentration ([Na+]i). Comparison of steady-state responses before (solid line) and after (dashed line) increasing [Na+]i from 10 to 14 mM. A: RA model; B: GP model.

beta -Adrenoceptor Stimulation

In the simulations of the beta -receptor stimulation we used the two known effects via the PKA. First, the L-type Ca2+ channels are phosphorylated, promoting enhanced Ca2+ influx (increase of the L-type current). Second, the phosphorylation of the regulatory protein of the SERCA, the phospholamban, leads to increased SR Ca2+ uptake. These mechanisms result in a faster relaxation but also accumulate Ca2+ into the SR and thereby promote increased Ca2+ release during excitation.

beta -Receptor stimulation was simulated by augmenting the ICa,L and by increasing the SERCA activity (Fig. 3). Both model cells have similar responses to beta -receptor stimulation, including Ca2+ accumulation in SR, which, in turn, leads elevated Ca2+ transients (2.12 µM in RA model and 2.10 µM in GP model) and prolongation of APD (APD90 increased to 64.0 ms from 50.1 ms in the RA model, and to 174 ms from 143 ms in the GP model). The mechanism of the AP lengthening is different in RA and GP models. In the RA model the AP lengthening was obviously caused by the INa/Ca augmentation (Fig. 3A, bottom trace), whereas in the GP model the AP duration increased because of the reduced (here Ca2+ dependent) inactivation of the ICa,L (Fig. 3B, third trace). The latter effect is the result of an increase in the maximal conductance of the L-type channels (to increase the current), when the Ca2+ transient-induced inactivation is countered and overcome by the increased voltage activation in the (now) longer APs.


View larger version (17K):
[in this window]
[in a new window]
  		Fig. 3.   Effects of beta -adrenoceptor stimulation [both L-type Ca2+ conductance and the activity of the sarco(endo)plasmic reticulum Ca2+- ATPase (SERCA) are increased]. Steady-state responses after simulation, control (solid line), simulated beta -adrenoceptor stimulation (dashed line). A: RA model; B: GP model.

Role of SR Ca2+ Content

The Ca2+ release and resulting Ca2+ transient seemed to excert a crucial influence on the AP shape in both models. Because the amount of Ca2+ released during excitation depends on the amount of the Ca2+ stored in SR (2, 3), we did the following simulation to evaluate the role of SR Ca2+ release in relation to all other studied mechanisms. To produce a Ca2+ transient increase the SR Ca2+ content was increased 20% in RA and 50% GP model cells (for scaling, see MATERIALS AND METHODS). At steady state, the peak of Ca2+ transient increased in both models, to 1.91 µM from 1.02 µM in the RA model and to 1.92 µM from 1.16 µM in the GP model (Fig. 4). In the RA model, the APD90 increased to 70.9 ms (27.9%) from 51.6 ms. In the GP model, APD90 shortened to 114 ms (20.9%) from 144 ms. In both models, AP duration changed without significant changes in [Na+]i or intracellular K+ concentration ([K+]i). The ionic mechanism underlying the prolongation of APD in the RA model is that the peak of increased [Ca]i overlaps the late repolarization, generating an enhanced inward INa/Ca together with a slight inactivation of ICa,L. A greater INa/Ca delays the repolarization at late phase of AP, resulting in the prolongation of late phase of AP. Meanwhile, in GP model cell, the increase of Ca2+ transient inactivates the ICa,L resulting the prominent shortening of the AP duration (Fig. 4). In the GP model, the enhanced inward INa/Ca in this situation has only minor impact on the shape of the AP.


View larger version (18K):
[in this window]
[in a new window]
  		Fig. 4.   Effects of increased sarcoplasmic reticulum (SR) Ca2+ content. Steady-state responses before (solid line) and after (dashed line) increasing Ca2+ in SR. A: RA model; B: GP model.

Clamping of ICa,L and INa/Ca

On the basis of the simulation of the present study, it seemed that the Ca2+ transient modulates the transmembrane currents differently in the RA and GP models. To further study this, we tried to separate the contribution of ICa,L and INa/Ca on the duration of AP during an enlarged Ca2+ transient (Fig. 5, A-D). By increasing the SR Ca2+ load (similarly as in Fig. 4), the Ca2+ transient was increased from ~1 to 2 µM in both models (Fig. 5, B and D). As previously shown, the increase of the Ca2+ transient decreased the AP duration in the GP model (Fig. 5A) but increased duration in the RA model (Fig. 5C), in traces marked "SR Caup-arrow ." The changes in APs were then analyzed further by clamping the enlarged Ca2+ transient at the same time as one of the key factors, either L-type current or the exchanger current was clamped to the same time course as the control situation. When the time course of ICa,L was clamped, this caused a shift of the APD in the GP model toward the control value (Fig. 5A, top trace). When time course of INa/Ca was clamped (Fig. 5A, bottom trace), the AP duration was shortened compared with control and with duration at higher Ca2+ transient. In identical simulations with the RA model (Fig. 5C), INa/Ca clamp reduced the AP duration. Meanwhile, when ICa,L was clamped, the APD was not significantly changed (traces marked as in Fig. 5A). The simulation suggests that in rat atrial cell, the prolongation of APD induced by elevated [Ca2+]i transient is mainly caused by the change in the INa/Ca rather than the sarcolemmal L-type current. In contrast, in the GP model clamping of INa/Ca little affected the duration of the AP with elevated [Ca2+]i transient, but the clamping of ICa,L forced the APD back to control value. This implies that the reduction of APD in the GP model induced by elevated [Ca2+]i is mainly contributed by the increased inactivation of the ICa,L rather than changes in the INa/Ca.


View larger version (21K):
[in this window]
[in a new window]
  		Fig. 5.   Relationships between form of the AP, [Ca2+]i, ICa,L, and INa/Ca during increase in Ca2+ stores. In this, APs (A and C) and Ca2+ transients (B and D) are shown for the GP model (A and B) and the RA model (C and D) with the control value (Control), and for when the Ca2+ transients were increased by increasing the Ca2+ in SR in the model as in Fig. 4 (SRCaup-arrow ). The contribution of the clamped currents to the change in duration of the AP could be separated by clamping the ICa,L and INa/Ca to their time courses under the control conditions (dashed-dotted and dotted lines, respectively, in A and C). Note that ICa,L clamp and Control traces are nearly identical in A, and same applies to the SRCa and Control traces in B.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The present investigation demonstrates the importance of Ca2+ influx and accumulation in SR in modulating the length of AP of cardiac myocytes during inotropic interventions. In the modeled cells, activation of SA channels, increase of the [Na+]i, and SR Ca2+ accumulation all caused qualitatively similar changes in the shape of AP and augmentation of the Ca2+ transient. In the AP model, all of these interventions caused lengthening of the AP, whereas in GP model AP duration decreased. In contrast, simulated beta -stimulation differs from all the other inotropic interventions because it produces AP lengthening in both models. We have built the simulations to keep the change in the Ca2+ transients about the same in all interventions, to facilitate comparison, and thus many effects, most probably that of beta -receptor stimulation may be more prominent in real cells. On the basis of simulations, we can suggest that whatever is the mechanism promoting the changes in the Ca2+ transient the change in the AP shape is significantly contributed by the increase of the Ca2+ transient. The results also implicated that the AP duration is controlled differently in cardiac myocytes with short and long AP duration during inotropic interventions.

Species-Specific and Cell-Type Differences in Regulation of AP Waveform by [Ca2+]i

The durations of APs are generally much shorter in atria than in ventricles. In the rat atrium, the presence of a relatively large depolarization-activated outward current rapidly repolarizes the membrane potential (6), causing a lack of a prominent plateau phase. A long plateau is a characteristic of ventricular APs in most species, such as the guinea pig, rabbit, human, and dog (22). The inactivation of L-type Ca2+ channels is partly voltage dependent, and therefore, the rapid repolarization of (rat) atrial APs should cause ICa,L to be inactivated faster than in the ventricles, as also observed by AP clamp in rat and rabbit (33). However, inactivation of ICa,L depends not only on membrane voltage but also on [Ca]i (33, 39). Because of the faster repolarization of rat atrial AP, the L-type Ca2+ channel inactivation is mediated predominantly by voltage-dependent inactivation, with little or no contribution of the Ca2+-dependent inactivation. Therefore, the inactivation of ICa,L is much more sensitive to increased Ca2+ transients in the guinea pig ventricle than in the rat atrium, as shown in the present simulation studies. On the other hand, Ca2+ release accompanying APs of short duration as seen in rat atria, leads to a situation where the peak of Ca2+ transient overlaps the late repolarization, resulting in a peak inward INa/Ca in late repolarization. Because of the plateau of the AP of the GP model, the Ca2+ transient triggers an INa/Ca that is of outward direction during the entire duration of plateau. This leads to fundamental differences in the AP regulation by Ca2+ transient in the RA and GP models. As a manifestation of this, Ca2+ transient augmentation leads to decrease of the AP duration in the GP model, whereas the same stimuli in the RA model results in an increase of the AP duration.

Role of Different Ca2+ Sources in AP Modulation

As shown in the present study, AP shape depends, among other things, on the source of Ca2+ producing the increase of the Ca2+ transient. In the RA model, the increase of the AP duration results from the augmentation of the Ca2+ transient via inward INa/Ca (Fig. 5). This effect shows no dependence on the source of Ca2+ producing the increase of the Ca2+ transient. However, in the GP model the AP shape depends strongly on the ICa,L. In the simulated beta -stimulation (Fig. 3), where ICa,L (and Ca2+ storage into SR) was increased (by increasing the maximal conductance), both models produced qualitatively similar changes in the AP, in line with the experimental findings from human atrial (18), guinea pig (21), and in rat ventricular cells (26). The mechanism of this was totally different in the RA model and the GP model. In the GP model, the AP lengthening was solely due to reduced inactivation of the L-type current caused by the increased voltage-dependent activation (Fig. 3). In the RA model, the AP is less dependent on the L-type current, and therefore, similar simulation strategy changes the AP by INa/Ca due to the increased Ca2+ transient.

Possible Physiological Implications

AP shape of the cardiac myocyte reflects concerted activation and inactivation of many ion channels and exchangers (3). In cardiac tissue, the length of APs also determines the excitability of the cells and the whole heart. Shortening or lengthening of AP can be proarrhythmic in the intact heart (32). The evident species-specific and atrial-ventricular-specific differences in the Ca2+-dependent regulation of the AP duration may cause confusion, when different animal models of the heart are used. For example, it has been shown that stretch of cardiac tissue produces Ca2+ transient augmentation in variety of cardiac preparations (1, 13, 14, 27, 30). The effect of stretch on the cardiac myocyte AP is, however, dependent on the species (and to some extent, on its atrial or ventricular origin). As suggested by the present study, in species with short AP duration (mouse and rat) Ca2+ transient increase shortens the AP (especially in the atrium), whereas in species with long AP (guinea pig, rabbit, and human), similar increase in the Ca2+ transient is likely to increase the duration (again, especially in the ventricles). As shown previously, in rat atrial myocytes stretch lengthens the AP (27, 28) and in species with long AP, a reduction of the duration has been reported (11, 23, 29, 31, 34). Because stretch is considered to be proarrhythmic (10, 16, 17), it is likely that the mechanism of stretch-induced arrhythmias is different in different species. The similar dispersion of the AP in response to other inotropics is likely to exist between different species. These include action of hormones (ET-1, angiotensin II, and epinephrine) and transmitters (norepinephrine), and experimental manipulations that augment Ca2+ transients. In addition, the impact of ion channel modulators (blockers or activators) on the AP probably depends on the species, as suggested previously (12, 25). It is also notable that the murine transgenic models are used to, e.g., simulate the pathogenesis of human heart. Because there are fundamental differences in the excitation-contraction coupling of the rat and humans, generalizations of the mechanisms and successful application of the results obtained with transgenic techniques, require understanding of these differences.

In summary, the contribution of Ca2+-dependent currents on the AP duration depends on the length of the AP. In short AP myocytes, Ca2+ transient augmentation promotes inward current via the Na+/Ca2+ exchange, which lengthens the AP. This effect is similar regardless of the mechanism causing the Ca2+ transient increase. In myocytes with long APs the increase of Ca2+ transients as such decreases the AP duration via Ca2+-dependent inactivation of the ICa,L. However, large increase in the L-type current increases the AP duration (as with beta -stimulation) despite the simultaneous Ca2+ transient augmentation.


    ACKNOWLEDGEMENTS

The authors are grateful for support from the Wihuri Foundation and the Finnish Cardiac Research foundation.


    FOOTNOTES

Address for reprint requests and other correspondence: M. Weckström, Dept. of Physical Sciences, Division of Biophysics, Univ. of Oulu, PO Box 3000, 90014 Oulun yliopisto, Finland (E-mail: Matti.Weckstrom{at}oulu.fi).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10.1152/ajpheart.00573.2001

Received 2 July 2001; accepted in final form 9 November 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Alvarez, BV, Pérez NG, Ennis IL, Camilió de Hurtado MC, and Cingolani HE. Mechanisms underlying the increase in force and Ca2+ transient that follow stretch of cardiac muscle. A possible explanation of the Anrep effect. Circ Res 85: 716-722, 1999.

2.   Bassani, JWM, Yuan W, and Bers DM. Franctional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. Am J Physiol Cell Physiol 268: C1313-C1329, 1995.

3.   Bers, DM. Excitation-contraction Coupling and Cardiac Contractile Force. Dordrecht, The Netherlands: Kluwer, 1991.

4.   Bers, DM. Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res 87: 275-281, 2000.

5.   Bluhm, WF, Lew WW, Garfinkel A, and McCulloch AD. Mechanisms of length history-dependent tesion in an ionic model of the cardiac myocytes. Am J Physiol Heart Circ Physiol 274: H1032-H1040, 1998.

6.   Boyle, WA, and Nerbonne JM. Two functionally distinct 4-aminopyridine-sensitive outward K+ currents in rat atrial myocytes. J Gen Physiol 1100: 1041-1067, 1992.

7.   Campbell, DL, Rasmusson RL, Comer MB, and Strauss HC. The cardiac calcium-independent transient outward potassium current: kinetics, molecular properties, and role in ventricular repolarization (2nd ed.). In: Cardiac Electrophysiology: From Cell to Bedside, edited by Zipes DP, and Jalife J.. Philadelphia, PA: Saunders, 1995, p. 83-96.

8.   Convery, MK, and Hancox JC. Comparison of Na+-Ca2+ exchange current elicited from isolated rabbit ventricular myocytes by voltage ramp and step protocols. Pflügers Arch 437: 944-954, 1999.

9.   Ferreo, FM, Saiz J, Ferrero JM, and Thakor NV. Simulation of action potentials from metabolically impaired cardiac myocytes, role of ATP-sensitive K+ current. Circ Res 79: 208-221, 1996.

10.   Franz, MR. Mechano-electrical feedback in ventricular myocardium. Cardiovasc Res 32: 15-24, 1996.

11.   Gannier, F, Beranengo JC, Jacquemond V, and Garnier D. Measurements of sarcomere dynamics simultaneously with auxotonic force in isolated cardiac cells. IEEE Trans Biomed Eng 40: 1226-1232, 1993.

12.   Hirota, K, Ito Y, Masuda A, and Momose Y. Effects of halothane on membrane ionic currents in guinea pig atrial and ventricular myocytes. Acta Anaesthesiol Scand 33: 239-244, 1989.

13.   Hongo, K, White E, Le Guennec JY, and Orchard CH. Changes in [Ca2+]i, [Na+]i and Ca2+ current in isolated rat ventricular myocytes following an increase in cell length. J Physiol (Lond) 491: 609-619, 1996.

14.   Hongo, K, White E, and Orchard CH. Effect of stretch on contraction and the Ca2+ transient in ferret ventricular muscles during hypoxia and acidosis. Am J Physiol Cell Physiol 269: C690-C697, 1995.

15.   Hussain, M, and Orchard CH. Sarcoplasmic reticulum Ca2+ content, L-type Ca2+ current and the Ca2+ transient in rat myocytes during beta -aderneergic stimulation. J Physiol (Lond) 505: 385-402, 1997.

16.   Lab, MJ. Contraction-excitation feedback in myocardium. Physiological basis and clinical relevance. Circ Res 50: 757-766, 1982.

17.   Lab, MJ. Mechanoelectric feedback (transduction) in heart: concepts and implications. Cardiovasc Res 32: 3-14, 1996.

18.   Li, GR, and Nattel S. Properties of human atrial ICa,L at physiological temperatures and relevance to action potential. Am J Physiol Heart Circ Physiol 272: H227-H235, 1997.

19.   Linz, KW, and Meyer R. Control of L-type calcium current during the action potential of guinea-pig ventricular myocytes. J Physiol (Lond) 513: 425-442, 1998.

20.   Luo, CH, and Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res 74: 1071-1096, 1994.

21.   Noguchi, K, Takahashi K, and Higuchi S. In-vitro negative chronotropic and inotropic effects of a novel dihydropyridine derivative, CD-832, in the guinea-pig: comparison with calcium-channel antagonists. J Pharm Pharmacol 50: 329-334, 1998.

22.   Opie, LH. The Heart Physiology, From Cell to Circulation. Philadelphia, PA: Lippincott-Raven, 1998.

23.   Reiter, M, Mann DE, and Williams GR. Interaction of hypokalemia and ventricular dilatation in isolated rabbit hearts. Am J Physiol Heart Circ Physiol 265: H1544-H1550, 1993.

24.   Shaw, RM, and Rudy Y. Electrophysiologic effects of acute myocardial ischemia: a mechanistic investigation of action potential conduction and conduction failure. Circ Res 80: 124-138, 1997.

25.   Song, Y, and Belardinelli L. Electrophysiological and functional effects of adenosine on ventricular myocytes of various mammalian species. Am J Physiol Cell Physiol 271: C1233-C1243, 1996.

26.   Tamada, A, Hattori Y, Houzen H, Yamada Y, Sakuma I, Kitabatake A, and Kanno M. Related articles effects of beta -adrenoceptor stimulation on contractility, [Ca2+]i, and Ca2+ current in diabetic rat cardiomyocytes. Am J Physiol Heart Circ Physiol 274: H1849-H1857, 1998.

27.   Tavi, P, Han C, and Weckström M. Mechanism of stretch-induced changes in [Ca]i in rat atrial myocytes. Circ Res 83: 1165-1177, 1998.

28.   Tavi, P, Han C, and Weckstrom M. Related articles intracellular acidosis modulates the stretch-induced changes in E-C coupling of the rat atrium. Acta Physiol Scand 167: 203-213, 1999.

29.   Tung, L, and Zou S. Influence of stretch on excitation threshold of single frog ventricular cells. Exp Physiol 80: 221-235, 1995.

30.   White, E, Boyett MR, and Orchard CH. The effects of mechanical loading and changes of length on single guinea-pig ventricular myocytes. J Physiol (Lond) 482: 93-107, 1995.

31.   White, E, Le Guennec JY, Nigretto JM, Gannier F, Argibay JA, and Garnier D. The effects of increasing cell length on auxotonic contractions: membrane potential and intracellular calcium transients in single guinea-pig ventricular myocytes. Exp Physiol 78: 65-78, 1993.

32.   Wolk, R, Cobbe SM, Hicks MN, and Kane KA. Functional, structural, and dynamic basis of electrical heterogeneity in healthy and diseased cardiac muscle: implications for arrhythmogenesis and anti-arrhythmic drug therapy. Pharmacol Ther 84: 207-231, 1999.

33.   Yuan, W, Ginsburg KS, and Bers DM. Comparison of sarcolemmal calcium channel current in rabbit and rat ventricular myocytes. J Physiol (Lond) 493: 733-746, 1996.

34.   Zabel, M, Koller BS, Sachs F, and Franz MR. Stretch-induced changes in the isolated heart: importance of the timing of stretch and implications for stretch-activated ion channels. Cardiovasc Res 32: 120-130, 1996.

35.   Zeng, J, and Rudy Y. Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys J 68: 949-964, 1995.

36.   Zeng, T, Bett GC, and Sachs F. Stretch-activated whole cell currents in adult rat cardiac myocytes. Am J Physiol Heart Circ Physiol 278: H548-H557, 2000.

37.   Zhang, YH, Youm JB, Sung HK, Lee SH, Ryu SY, Lee SH, Ho WK, and Earm YE. Stretch-activated and background non-selective cation channels in rat atrial myocytes. J Physiol (Lond) 523: 607-619, 2000.

38.   Zhou, Z, and Bers DM. Ca2+ influx via the L-type Ca2+ channel during tail current and above current reversal potential in ferret ventricular myocytes. J Physiol (Lond) 523: 57-66, 2000.

39.   Zuhlke, RD, and Reuter H. Ca2+-sensitive inactivation of L-type Ca2+ channels depends on multiple cytoplasmic amino acid sequences of the alpha1C subunit. Proc Natl Acad Sci USA 95: 3287-3294, 1998.

Am J Physiol Heart Circ Physiol 282(3):H1047-H1054
0363-6135/02 $5.00 Copyright © 2002 the American Physiological Society


This article has been cited by other articles:


Home page
 Phil Trans R Soc AHome page
J. T. Koivumaki, J. Takalo, T. Korhonen, P. Tavi, and M. Weckstrom
Modelling sarcoplasmic reticulum calcium ATPase and its regulation in cardiac myocytes
Phil Trans R Soc A, June 13, 2009; 367(1896): 2181 - 2202.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
S. C. Hao, D. J. Christini, K. M. Stein, P. N. Jordan, S. Iwai, O. Bramwell, S. M. Markowitz, S. Mittal, and B. B. Lerman
Effect of {beta}-adrenergic blockade on dynamic electrical restitution in vivo
Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H390 - H394.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
C. I. Spencer and J. S. K. Sham
Effects of Na+/Ca2+ exchange induced by SR Ca2+ release on action potentials and afterdepolarizations in guinea pig ventricular myocytes
Am J Physiol Heart Circ Physiol, December 1, 2003; 285(6): H2552 - H2562.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
282/3/H1047    most recent
00573.2001v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (10)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Han, C.
Right arrow Articles by Weckström, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Han, C.
Right arrow Articles by Weckström, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online