© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
The role of L-type calcium current in the generation of repolarization-induced contraction in cardiac myocytes
Imperial College School of Medicine at National Heart & Lung Institute, London, UK
* Corresponding author. Tel.: +44-171-352-8121; fax: +44-171-351-8145 r.egdell{at}hotmail.com
Received 18 April 2000; accepted 24 May 2000
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Abstract |
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Objective: Early experiments into the arrhythmogenic transient inward current frequently showed apparent coupling of this current to repolarization from a depolarizing voltage clamp step. Calcium transients have subsequently been shown to couple to such repolarization and are the result of calcium release from the sarcoplasmic reticulum. We have investigated whether this phenomenon is due to calcium entry via non-inactivated calcium channels or to voltage-activated SR release. Methods: Voltage clamp steps were imposed on isolated guinea pig and rabbit cardiac myocytes. Calcium release was monitored by tracking cell contraction. L-type calcium current at the moment of repolarization was manipulated by the rapid application of 2 mM cadmium or 10 mM calcium. Results: Repolarization-induced contraction was abolished by the rapid application of 2 mM cadmium immediately prior to repolarization, and was augmented by the rapid change of extracellular calcium concentration from 2 mM to 10 mM immediately prior to repolarization. There is no evidence of coupling of drive train-induced aftercontractions to repolarization from the final action potential of the drive train and 2 mM cadmium does not alter the appearance or timing of these aftercontractions. Simulation of phase 1 repolarization in the mammalian cardiac action potential decreases rather than increases twitch amplitude. Conclusion: Repolarization-induced contraction results from calcium entry through non-inactivated calcium channels, not from voltage-activated release. It plays no physiological role in contributing to the stimulated twitch and no pathological role in generating drive train-induced aftercontractions.
KEYWORDS Ca-channel; Calcium (cellular); Membrane currents; Myocytes; SR (function)
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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In cardiac myocytes, depolarization of the cell membrane at the onset of the action potential results in the release of calcium from the sarcoplasmic reticulum (SR) in response to the influx of calcium across the sarcolemma (‘calcium-induced calcium release’, CICR) [1,2]. While investigating the voltage-dependence of calcium transients, two groups described small rises in intracellular calcium concentration in response to repolarization from depolarized clamp steps [3–5], which was shown to involve calcium release from the SR [3]. Because L-type calcium channels have never been shown to be activated by repolarization, alternative explanations were sought for this phenomenon and two possibilities were considered. Firstly, a proportion of L-type calcium channels might fail to inactivate during the clamp steps. When the membrane is repolarized, the electrochemical gradient for calcium is greatly increased, leading to transitory calcium entry before the calcium channels become voltage-inactivated. The second possibility considered was that of direct voltage-sensitive release of calcium from the SR. The voltage-sensitive theory was rejected in favour of the non-inactivated calcium channel theory partly because the voltage dependence of repolarization-induced SR release closely matched the voltage-dependence of CICR and partly because CICR was a well established mechanism of SR release in cardiac myocytes, whereas there was no evidence at the time for a voltage-activated release mechanism. However, more recent evidence has been presented that cardiac myocytes may exhibit voltage-activated SR calcium release upon depolarization [6,7]. A more careful examination of the mechanism of repolarization-induced SR release is therefore warranted to distinguish between the two theories.
A closely related phenomenon is to be found in early studies of the transient inward current which accompanies spontaneous release of calcium from the SR. When voltage clamp pulses were used to load the preparations with calcium (via reverse mode sodium–calcium exchanger activity), the transient inward current often appeared to be coupled to repolarization of the clamp step. In some studies, the authors specifically comment on this phenomenon [8–10], whereas in others it is simply apparent by examination of the traces [11–13]. In studies which employed two-step repolarizations from clamp step pulses, transient inward currents were apparent after each repolarization [9,14]. These findings seem at odds with the concept of the transient inward current accompanying ‘spontaneous’ release of calcium from the SR. Two possibilities need to be considered. Firstly, despite a number of authors’ reports of apparent coupling to repolarization, these calcium transients may in fact be truly spontaneous, any coupling being fortuitous. A formal demonstration that there is genuine coupling to repolarization is therefore needed. Secondly, if the calcium transients are triggered by repolarization and are not spontaneous, then the relevance of these phenomena to drive train-induced aftercontractions, believed to underlie a proportion of clinical arrhythmias, must be questioned. We have sought to confirm the existence of the phenomenon, to investigate its mechanism and to establish its relevance to drive train-induced arrhythmogenicity.
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2 Methods |
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Left ventricular myocytes were isolated from male guinea pigs using a previously described enzymatic process [15] and from male rabbits using a process which differed only in that collagenase was applied at a concentration of 0.5 mg/ml rather than 0.3 mg/ml and the first two incubations were performed for 10 min rather than 5 min. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Cells were superfused with normal Tyrode's solution, containing (mM) NaCl 140, KCl 6, CaCl2 2, MgCl2 1, Glucose 10, N-2-hydroxyethylpiperazine-N'-2-ethanesulphonic acid (HEPES) 10, pH adjusted to 7.4 using NaOH, at 22°C. Cells were impaled with high resistance glass microelectrodes filled with 2 M KCl, 10 mM HEPES and 100 µM ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), pH adjusted to 7.2 using KOH.
To generate aftercontractions, cells were subjected either to rapid drive trains or to voltage clamp pulses. During rapid drive trains, cells were stimulated with 10 ms current pulses of amplitude 50% above threshold for 20 beats, to ensure that steady-state was reached, at frequencies sufficient to induce aftercontractions (typically around 1.0 Hz). Voltage clamping was achieved by switch clamping using sampling rates of 5–10 kHz. To standardise SR loading conditions when voltage clamp pulses were employed, test pulses were preceded by a conditioning train of 10 clamp pulses from a holding potential of –80 mV at 0.5 Hz. For experiments on rabbit cells, conditioning train pulses consisted of 500 ms steps to 0 mV. In guinea pig cells such a conditioning train sometimes induced calcium overload such that aftercontractions occurred during the conditioning train or between the train and the test pulse. In these cells, conditioning pulses to +60 mV or –20 mV were used to reduce calcium influx via L-type calcium channels. For a given cell, identical conditioning trains were used for each run of an experiment. The test pulse was delivered 1500 ms after the end of the conditioning train and consisted of a step from –80 mV to +60 mV, followed by repolarization to –80 mV. The duration of the test pulse was varied in the experiments illustrated in Fig. 1. In all other experiments, a test pulse duration was used which generated a distinct, identifiable repolarization-induced aftercontraction. This duration differed between cells, but was held constant for each experimental run on the same cell.
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In some experiments, rapid solution switches (delay to solution delivery 100–200 ms) were made immediately prior to repolarization from a test pulse. The intention with these experiments was to change the SR calcium content of the cell as little as possible while altering the behaviour of the L-type calcium channel at the moment of repolarization. The solutions delivered in this way consisted of a solution containing 2 mM cadmium (added directly to the above Tyrode's solution) and a ‘high calcium’ solution (as the above Tyrode's solution but with 10 mM calcium instead of 2 mM).
Cell shortening was recorded using a video-based edge detection system [16]. Aftercontraction amplitudes were measured from a point immediately prior to the onset of the aftercontraction to its peak. Drive trains, voltage clamp protocols and solution switches were controlled by pCLAMP6 software (Axon Instruments).
Data are expressed as mean±SEM, unless otherwise indicated. Groups are compared by t test and a probability level <0.05 is considered significant.
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3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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3.1 Correlation between repolarization and contraction
Examples of repolarization-induced contractions are shown in Fig. 1. Fig. 1A illustrates cell shortening responses to clamp steps of varying durations in a representative guinea pig myocyte. A clamp step of 1500 ms induces a contraction apparently coupled to repolarization. A longer step of 3500 ms induces a spontaneous contraction during the step, followed by a smaller contraction apparently coupled to repolarization. Fig. 1B illustrates cell shortening responses to clamp steps of varying durations in a representative rabbit myocyte. Following a step of 1400 ms, it is impossible to resolve any repolarization-induced contraction from the relaxation phase of a small tonic contraction, possibly due to sodium–calcium exchanger-mediated calcium entry. A clamp step of 2500 ms is accompanied by a contraction apparently coupled to repolarization, while a longer step of 4500 ms induces a spontaneous contraction during the step. Times of aftercontraction onset and peak for all clamp step durations investigated in these two cells are shown in Fig. 1C (guinea pig) and 1D (rabbit). In the case of multiple aftercontractions (as in Fig. 1A), the timing of only the first aftercontraction is shown. The rabbit cell, in common with the majority of rabbit cells investigated, shows a triphasic response to clamp step duration. At the shortest durations tested, up to 1600 ms, no phasic contraction is apparent. At intermediate clamp step durations, from 1600 ms to 2600 ms, there is a contraction induced by the clamp step which is tightly coupled to repolarization (correlation coefficient, R = 0.99, P<0.0001 between aftercontraction onset time and clamp step duration). At the longest clamp step durations tested, over 2600 ms, spontaneous contractions occur during the clamp step at approximately the same time, irrespective of the clamp step duration. The guinea pig cell (Fig. 1C) lacks the initial phase, in common with the majority of guinea pig cells investigated. Even at short step durations (down to 100 ms) a contraction coupled to repolarization is apparent. Up to a step duration of 1800 ms, contractions are tightly coupled to repolarization (correlation coefficient, R = 0.99, P<0.0001 between aftercontraction onset time and clamp step duration). At longer step durations than this, spontaneous contraction timing is independent of clamp step duration, occurring at approximately the same time during the clamp step.
The correlations between clamp step duration and first aftercontraction onset time for all cells investigated are illustrated in Fig. 2A. For this analysis, only clamp steps which induce an aftercontraction following the end of the clamp step are included (i.e. the second phase of the triphasic relationship to clamp step duration discussed above). In guinea pig cells, R = 0.99, P<0.0001. In rabbit cells, R = 0.99, P<0.0001. In these experiments, no example was seen of a first aftercontraction occurring after repolarization of the step without being closely coupled to it. In contrast, aftercontractions induced by rapid drive trains usually occur after repolarization of the final action potential of the drive train without any apparent coupling to it. To quantify this, guinea pig cells were subjected to rapid drive trains to induce aftercontractions. In 88 rapid drive trains in 30 cells which generated aftercontractions, the onset time of the aftercontraction, measured relative to the final stimulus of the drive train, was correlated with the duration of the final action potential of the train. This relationship is illustrated in Fig. 2B. There is no significant correlation between the two variables (P = 0.26).
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The onset of aftercontractions following voltage clamp steps occurred 66±8 ms after repolarization in rabbit, 49±3 ms in guinea pig (P = 0.046). The amplitude of repolarization-induced aftercontractions was positively correlated with clamp step duration within individual cells. The guinea pig cell illustrated in Fig. 1A and Fig. 1C showed a correlation coefficient between clamp step duration and aftercontraction amplitude of 0.95, P = 0.0036. The correlation coefficient for the rabbit cell illustrated in Fig. 1B,D was 0.86, P = 0.027.
3.2 Voltage-dependence of repolarization-induced aftercontractions
The voltage-dependence of repolarization-induced aftercontractions was investigated by repolarizing guinea pig cells from the +60 mV test pulse to different potentials from –160 mV to +50 mV. Representative traces are displayed in Fig. 3A. Repolarization-induced aftercontraction amplitude is maximal at 0 mV, and declines at more positive and more negative potentials. Fig. 3B shows a contraction–voltage curve for all nine cells investigated in this way, confirming a maximal aftercontraction amplitude at 0 mV. This finding is identical to the relationship between repolarization voltage and calcium transient as measured with fura-2 by Beuckelmann & Wier [5]. The voltage-dependence of repolarization-induced calcium transients and aftercontractions is reminiscent of the I–V curve for L-type calcium current. However, this pattern of voltage-dependence might also be consistent with a voltage-sensor. The following experiments were therefore undertaken to distinguish between these two possibilities.
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3.3 The role of non-inactivated calcium channels
Cadmium was rapidly applied to cells shortly before repolarization from clamp steps. Cadmium is a non-selective blocker of L-type calcium channels, also partially blocking the sodium–calcium exchanger at the concentration used (2 mM). Experiments were attempted using the selective blockers nifedipine and verapamil. However, under our experimental conditions, both agents showed use-dependency, requiring 4–5 depolarizing clamp steps before full blockade of calcium current was seen. Cadmium was therefore used in preference, to achieve rapid and reversible blockade of calcium current. The results of cadmium application are illustrated in Fig. 4. Cadmium application rapidly abolishes calcium current, as shown in Fig. 4A. In this example, a small inward current remains in response to a clamp step from –40 to 0 mV 300 ms after cadmium application, but is absent when the same step is applied 500 ms after switching to cadmium. The timing of cadmium applications prior to repolarization from a test pulses to +60 mV was based on experiments of this type, and was 623±154 ms (mean±SD) in 12 cells. A representative set of traces is shown in Fig. 4B. This rabbit cell demonstrated a large repolarization-induced aftercontraction following a clamp step of 3000 ms which was abolished by the application of cadmium 600 ms prior to repolarization. It is important to note that a repolarization-induced aftercontraction is present after a step of 2000 ms. This shows that the abolition of the aftercontraction by cadmium is not because of decreased SR content secondary to cadmium blocking reverse mode sodium–calcium exchange during the depolarized step, since the cadmium is not applied until after a time at which the cell has been shown to be capable of exhibiting a repolarization-induced aftercontraction. Pooled data from eight rabbit and five guinea pig cells are shown in Fig. 4C. Cadmium abolished repolarization-induced aftercontractions in every case. In each experiment, cadmium was only applied after a time at which a repolarization-induced aftercontraction had been demonstrated in that cell.
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Fig. 5 illustrates the effects of 2 mM cadmium on aftercontractions induced by rapid drive trains in guinea pig cells. Representative traces of cell shortening following 20-beat drive trains are shown in Fig. 5A. In the same cell, after identical drive trains, spontaneous aftercontractions occur irrespective of whether cadmium is applied following relaxation from the final stimulated twitch of the train. Pooled data for all 13 cells studied in this way (Fig. 5B) show that there is no difference in the onset or peak times of drive train-induced aftercontractions in the presence or absence of cadmium.
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High calcium solution (10 mM) was rapidly applied to cells immediately prior to repolarization from clamp steps, to increase the electrochemical gradient for calcium entry at the moment of repolarization. The most attractive tool for achieving this would seem to be the selective calcium channel agonist Bay K 8644. Experiments with this agent showed no use dependence, but its effect on L-type calcium current nonetheless took 15 to 20 s to take effect. This prevented use of the agent in a rapid switching fashion prior to repolarization of a test clamp step.
The potential problem with the use of high calcium solution is that the cell membrane is exposed to a higher extracellular calcium concentration at a time when the sodium–calcium exchanger is expected to be operating in reverse mode leading to calcium influx into the cell. Thus any increase in repolarization-induced aftercontraction amplitude resulting from the application of high calcium solution prior to repolarization might be due to increased SR calcium content rather than any effect upon the trigger to SR release. To overcome this problem we applied high calcium solution to the cell for one second at two different times during the test clamp step, on separate runs. On one occasion the high calcium was applied for one second at the beginning of the clamp step, on the other occasion the high calcium solution was applied one second before repolarization from the clamp step. The effect of these applications on SR load should be approximately the same, but with the second application repolarization takes place with high calcium solution outside the cell and hence an increased electrochemical driving force for calcium across the cell membrane.
Fig. 6A demonstrates representative traces from a guinea pig cell which was subjected to a clamp step to +60 mV under control conditions (left-hand panel), with 10 mM calcium solution applied during the first second of the clamp step (middle panel) and with 10 mM calcium solution applied during the last second of the clamp step (right-hand panel). The application of high calcium solution is accompanied by a markedly increased rate of tonic contraction. There is some relaxation following a return to normal calcium solution, which is not present in the right-hand panel. Because this may cause an apparent increase in aftercontraction amplitude with respect to baseline, since the aftercontraction starts from a more contracted level, amplitudes were measured from the moment of repolarization to peak as well as from peak to the baseline after relaxation. By either measure of aftercontraction amplitude, the aftercontraction occurring when high calcium solution was applied late in the step is larger than control or when high calcium solution is applied early in the step. Pooled data for all eight guinea pig cells investigated in this way are presented in Fig. 6B. Aftercontraction amplitude is higher when high calcium solution is applied late in the step than when it is applied early or under control conditions.
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3.4 Physiological relevance of repolarization-induced contraction
The above experiments suggest that repolarization-induced aftercontractions occur following voltage clamp steps, but are not relevant to the generation of drive train-induced aftercontractions. The final question that was addressed was whether repolarization-induced contraction might play a role in generating the stimulated twitch. The normal guinea pig action potential exhibits a phase 0 ‘overshoot’, during which the potential rises to around +40 mV, before partially repolarizing to the plateau voltage (phase 1). If repolarization-induced contraction has any physiological relevance, phase 1 repolarization early in the action potential might be responsible for a proportion of the twitch. This was tested by subjecting guinea pig cells to voltage clamp pulses, following conditioning trains, as illustrated in Fig. 7A, top panel. The membrane potential was clamped to +60 mV for 0, 5, 10 or 50 ms, before being repolarized to 0 mV for the remainder of a 500 ms step. Fig. 7B shows representative cell shortening traces for one cell in response to the four clamp step protocols. The presence of an initial potential of +60 mV reduced the amplitude of the resulting twitch as compared with the step without this initial potential (i.e. ‘a’=0). The twitch amplitude was inversely proportional to the duration of the initial +60 mV step. Pooled data for all six cells investigated in this way are shown in Fig. 7B. An initial step to +60 mV reduced cell shortening, suggesting that repolarization-induced contraction plays no part in generating the stimulated twitch.
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
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Having confirmed the phenomenon of repolarization-induced contraction, we have attempted to distinguish between the possible mechanisms by manipulating the behaviour of calcium channels immediately prior to repolarization. Repolarization-induced contraction is abolished by the rapid application of 2 mM cadmium and augmented by the rapid application of 10 mM calcium. One potential confounding effect of cadmium is its recently described inhibitory effect on the SR calcium release channel [17]. The time course of this blockade, however, is several minutes. Since cadmium was applied for only 623±154 ms (mean±SD) prior to repolarization, we expect no significant inhibitory effect on SR release.
Because of the effects of the solution switches on the sodium–calcium exchanger, these experiments do not allow us to distinguish between calcium entry via calcium channels and calcium entry via the exchanger at the moment of repolarization. However, repolarization from +60 mV to –80 mV would be expected to increase the electrochemical driving force for calcium entry through calcium channels but decrease calcium entry through the exchanger. Similarly, we cannot exclude the possibility that repolarization-induced SR release results from a voltage-sensor which is sensitive to extracellular divalent cations. However, the simplest explanation for these data is that the phenomenon is attributable to non-inactivated L-type calcium channels.
Further evidence for a role for calcium channels rather than a voltage-sensor comes from the experiments illustrated in Fig. 7 in which phase 1 repolarization is simulated by a voltage clamp protocol. Voltage-sensitive SR release, resulting from the 60 mV repolarization might be expected to lead to an increase in the resulting twitch as compared with a clamp step without an initial overshoot to +60 mV. In contrast, repolarization-induced calcium entry would certainly occur at the end of the initial +60 mV step, but would be no greater than calcium entry at that point in the absence of such a step. Since calcium entry would be inhibited during the +60 mV step, because of the reduced electrochemical calcium gradient across the membrane, a decline in twitch amplitude might be expected as the result of a simulated overshoot to +60 mV. As shown in Fig. 7, the results followed the latter pattern.
In conclusion, our data support the previous suggestion that repolarization-induced SR calcium release results from trans-sarcolemmal calcium entry via non-inactivated calcium channels [3–5]. The presence of this phenomenon does not in itself support the existence of voltage-sensitive SR calcium release in cardiac myocytes [6,7], but does not rule out the possibility of such a mechanism contributing to depolarization-induced calcium release. Repolarization-induced contraction is entirely an experimental phenomenon, neither contributing to the stimulated twitch nor the genesis of spontaneous drive train-induced aftercontractions. We suggest that experimental studies which investigate the arrhythmogenic transient inward current by means of voltage clamp steps [8–14] should be interpreted with caution since the mechanism of SR calcium release may differ from the situation which exists during afterdepolarization-related arrhythmias.
Time for primary review 27 days.
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Acknowledgements |
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We thank Mr. P. O'Gara for his expert assistance with myocyte isolation. R.E. was supported by a fellowship from the Medical Research Council.
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