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Kamkin A, Kiseleva I, editors. Mechanosensitivity in Cells and Tissues. Moscow: Academia; 2005.

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Mechanosensitivity in Cells and Tissues.

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Role of Stretch-activated Channels in the Heart: Action Potential and Ca2+ Transients

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Accepted ; Received February 15, 2005.

The heart contraction is preceded by the excitation of cardiomyocytes. Conversely, a myocardial contraction can modulate the excitation of cardiomycytes by alteration of the action potential and Ca2+ transients. This modulation is generally referred to as a mechano-electric feedback. Stretch-activated channels have been suggested as a possible mechano-transducer of the mechano-electric feedback. The channel properties such as ionic selectivity, voltage-dependence and stretch-dependence have been studied on the channel to clarify its roles in the generation of stretch-induced changes in electrical activity and Ca2+ transients. In spite of technical difficulty and some contradictory results between investigators, there are increasing evidences convincing the stretch-activated channel as the mechano-transducer of the mechano-electric feedback. We will discuss recent progress in this issue and some simulation results will be presented here to demonstrate the role of stretch-activated channels based on the experimental findings from the rat atrial myocytes.


The electrical activity in the cardiac cells initiates heartbeat, which is generally known as the excitation-contraction coupling. In addition, the heart has a potential to regulate its cellular electrical activity in response to the changes in contractile state or volume load [25, 48, 49]. The regulatory control system is generally referred to as a mechano-electric feedback or transduction [45, 49]. The stretch-regulated electrical activities include an alteration of the action potential shape such as diastolic depolarization [9, 27], lengthening [6, 71, 78] or shortening of the action potential duration (APD) [15, 22, 26, 69], afterdepolarization [26, 33, 46] and premature excitation [26, 27, 66].

The mechanical stretch has also been known to induce changes in myocardial resting [Ca2+]i [28, 29, 51, 76] or Ca2+ transients [3, 41, 71] which are deeply related to the stretch-induced changes in electrical activity as well as the contractile force. The increase in the amplitude of Ca2+ transients is generally thought to represent the slow response, a length-dependent change in contractile state, whereas the rapid response is caused by the length-dependent myofilament Ca2+ sensitivity [2].

Since the first discovery in chick skeletal muscles by Guharay and Sachs [31], stretch-activated channels (SACs) have been proposed as a probable mechano-transducer of the mechanical stimulus in a cellular level [37]. Channel properties such as ionic selectivity, voltage-dependence and stretch-dependence have been studied in both the single-channel and whole-cell level. SACs usually have non-selectivity to cations and voltage-independent activation when activated by a direct stretch using carbon fibres or microelectrodes [63, 79]. There are growing evidences that major stretch-induced changes in electrical activity are mediated by activation of these channels [12, 21, 44]. The involvement of SACs in the stretch-induced arrhythmias and diastolic depolarization was demonstrated by using a specific blocker [8].

Since SACs have a permeability for Ca2+ as well as monovalent cations, the activation of SACs has been proposed to mediate a stretch-induced rise in the resting [Ca2+]i and Ca2+ transients [12, 43, 64, 60]. The activation of SAC was also suggested to induce Na2+ accumulation with its non-selectivity over cations [38]. The changes in [Na+]i was thought to increase [Ca2+]i via the activation of Na+-Ca2+ exchangers operating in a reverse-mode [3, 14, 40].

A more complicated circumstance is that the action potential and Ca2+ transients are not independent each other [32]. The ion channels or exchangers dependent on the [Ca2+]i are generally suggested to couple these two cellular events. The interaction of action potential and Ca2+ transients makes it difficult to interpret those complex cellular events induced by mechanical stretch.

Considerable progress in the mathematical cell-models has made it possible for us to simulate and predict very complex biological process with ease. Recently, Noma's group has made a cardiac cell model (Kyoto-Model) to describe various cellular activities such as action potential, Ca2+ transients and contractile force [53, 62]. Combining Kyoto-Model and experimental findings on SACs in rat atrial myocytes, we were able to reproduce the effect of mechanical stretch on the electrical activity and Ca2+ transients. The objective of this article is to review and summarize advances in the effect of mechanical stretch on the heart by using a more comprehensive tool, a mathematical cell-model.

Mode of stretch: Uniaxial mechanical stretch

The methods to stretch cardiac preparations have been extensively reviewed by Cazorla et al. [19]; our talk will be focused on the methods of uniaxial mechanical stretch of single cardiomyocytes. Physiologically, a mechanical stretch in the heart is induced by changes in diastolic volume or peripheral resistances, where the cells are stretched in their long and short axes (x- and y-axis) [19]. In addition to stretch, the compression is also applied to the cell membrane in the second short axis (z-axis). The method of mechanical stretch in the long and short axes (biaxial stretch) of cells was originally developed by Banes et al. [5], where the cells were grown and stretched on the culture plates made of flexible bottom by applying a vacuum. In the case of uniaxial mechanical stretch, the stretch usually begins with attachment of two patch pipettes to each end of a cell. The cell is then stretched to its longitudinal direction by displacement of one patch pipette relative to the other fixed patch pipette. This technique was originally developed by Brady et al. [10] and established by Sasaki et al. [63] and Wellner and Isenberg [74]. Carbon fibres have been also frequently used instead of patch pipettes to allow simultaneous measurement of a length change by cell contraction as well as the electrical activity and Ca2+ transients [18, 36, 50, 76].

Fig. 1 demonstrates a typical example of a uniaxial mechanical stretch applied to the single rat atrial myocyte using two patch pipettes. Both the pipettes were sealed to the membrane by applying a negative pressure. The stretch was performed by the displacement of one patch pipette attached to an end of myocyte in a longitudinal direction, using a hydraulic micromanipulator (Narishige, Japan). In this case, the sarcomere pattern was relatively uniform across the cross-striations between two patch pipettes before and after the stretch, which suggested that this technique generated a uniform stretch. The extent of stretch can be expressed as a percentile change in cell length (Lstretch - Loriginal) relative to the original cell length (Loriginal):

Image ch12_youme1.jpg
There is a technical difficulty in using this technique on a conventional patch-clamp study; the seal between the membrane and patch pipette is frequently disrupted by the cell stretch giving out false positive results. Furthermore, Kamkin et al. [40] showed that the method does not lengthen the individual sarcomere length homogenously across the cell from the surface to the bottom. In the study, the extent of deformation decayed from the upper surface towards the bottom of the cell. However, uniaxial mechanical stretch has some advantages, easy control and quantify of the degree of stretch [79]. Since the directionality of the stretch is unidimensional, the degree of stretch is simply determined as a percentile change in length by longitudinal displacement of a patch pipette as shown in the equation (1). Compared to the stretch of a multicellular preparation, the uniaxial stretch of the single myocytes is easier to study the effect of the stretch without considering the influence of other non contractile network (collagen, elastin, nerve terminals etc) on the muscle contraction [30, 56]. The uniaxial stretch is also generally assumed to be the most appropriate model analogous to the stretch of tissue [11]. Furthermore, it also gives the opportunity to perform a detailed electrophysiological experiment.

Figure 1. Demonstration of a uniaxial mechanical stretch.

Figure 1

Demonstration of a uniaxial mechanical stretch. A - image obtained when two patch pipettes were attached to each end of a cell. Cross-striations are visible. B - image obtained after the upper pipette was moved in the longitudinal direction by 15 % of (more...)

Changes in electrical activity of the heart with stretch

Effects of mechanical stretch on resting membrane potential

There are evidences that the mechanical stretch induces a depolarization of the resting membrane potential in isolated rabbit hearts [27], canine hearts [26, 66], guinea-pig hearts [55], ventricles of artificially ventilated rats [9], single frog ventricular cells [73] and in situ canine hearts [26]. The diastolic depolarizations by uniaxial stretch of the single cardiomyocytes were also reported in isolated ventricular myocytes from the mice [40], humans, rats and guinea-pigs [39, 78] and in isolated atrial myocytes from rats [79]. In most cases, the magnitude of the depolarization was dependent on the degree of stretch. However, there are also evidences that mechanical stretch does not affect the resting membrane potential in the guinea-pig ventricular myocytes in response to axial stretch [6]. Nakagawa et al. [54] reported a more complicated case where mild to moderate stretches induce depolarizations whereas severe stretches induce hyperpolarizations in guinea pig ventricular muscles. They explained such that the hyperpolarizations induced by severe stretches are probably mediated by the increase in potassium conductance, presumably secondary to the increase in [Ca2+]i.

In general, the opening of SACs has been used to explain the diastolic depolarization by mechanical stretch [49, 79]. Single channel studies by Kim [42, 43] demonstrated the existence of a nonselective (Na+, K+ and Ca2+) and K+-selective SACs in rat atrial myocytes. The whole-cell and single channel studies by Zhang et al. [79] also demonstrated the existence of stretch-activated non-selective cation channels in rat atrial myocytes. Fig. 2 demonstrates the whole-cell currents (ISAC) carried through stretch-activated non-selective cation channels as a current-voltage relationship. The reversal potential of ISAC was -6.1 ± 3.7 mV (n = 7). The whole-cell currents (ISAC) with similar characteristics were also obtained from the guinea-pig [63, 39], human [39] and mouse ventricular myocytes [40]. Considering the value of reversal potential, the activation of ISAC should lead to a depolarization of resting membrane potential.

Figure 2. Effect of a longitudinal mechanical stretch on the stretch-activated current (ISAC).

Figure 2

Effect of a longitudinal mechanical stretch on the stretch-activated current (ISAC). I–V relationships of ISAC in normal Tyrode external and high-K+ internal solutions. Left upper inset shows the chart recording of current traces. Currents were (more...)

As an alternative mechanism of diastolic depolarization with mechanical stretch, a modulation by Ca2+–dependent ion channels could be suggested. Ehara et al. [24] identified a class of Ca2+-activated non-selective cation channel using cell-attached and inside-out patch clamp technique in guinea-pig ventricular myocytes. Activation of these channels is thought to depolarize the resting cell membrane. Therefore, it could be suggested that the Ca2+ entry during a mechanical stretch [2] might depolarize the diastolic cell membrane of the heart via an activation of Ca2+-activated non-selective cation channel. However, experimental findings, which associate the diastolic depolarization with the activation of Ca2+-activated non-selective cation channels in the whole-cell level, are still lacking. This hypothesis remains to be studied as a possible mechanism of stretch-induced diastolic depolarization.

Franz et al. [26, 27] found that applying rapid volume pulses to isolated canine hearts produces premature ventricular extrasystoles. Stacy et al. [66] also found that diastolic stretch increases stretch-induced depolarization and arrhythmia. They explained the mechanism as such; as the degree of stretch becomes larger, the diastolic depolarization reaches a threshold to trigger an action potential. They also suggested that this mechanism is important in the generation of stretch-induced arrhythmia. The involvement of SACs in the generation of diastolic depolarization and stretch-induced atrial arrhythmias was demonstrated by using gadolinium [7] or more specific blocker isolated from the venom of the tarantula Grammostola spatulata [8]. Fig. 3 shows an example of diastolic depolarization which eventually triggers an action potential during a mechanical stretch. Action potentials induced by mechanical stretch were smaller in the amplitude compared with those induced by current injection. The reduction in the action potential amplitude is possibly induced via the partial inactivation of voltage-gated sodium channels during the slow depolarization to the threshold level [79].

Figure 3. Effect of a mechanical stretch on the resting membrane potential, action potential in rat atrial myocytes.

Figure 3

Effect of a mechanical stretch on the resting membrane potential, action potential in rat atrial myocytes. The mechanical stretch with two patch pipettes depolarized the resting membrane potential. As the depolarization reaches a threshold (arrow), an (more...)

In order to illustrate the role of ISAC in the stretch-induced diastolic depolarization and action potential firing, a simulation was conducted based on experimental data from Zhang et al. [79]. Mathematical equations are described in Appendix. Fig. 4 clearly demonstrates an example of simulation showing the diastolic depolarization and stretch-induced firing of an action potential by incorporation of the SACs into an electrophysiological cell model of rat atrial myocytes. The degree of diastolic depolarization was dependent on the channel conductance and the diastolic depolarization above a threshold level triggered an action potential in agreement with the experimental results. The action potential amplitude was dependent on the speed of depolarization, which determines the degree of inactivation of voltage-gated sodium channels affecting the overshoot of action potentials (see overshoot potentials of c and d in Fig. 4).

Figure 4. Changes in membrane potential during a membrane stretch with different conductance of SACs in a model simulation.

Figure 4

Changes in membrane potential during a membrane stretch with different conductance of SACs in a model simulation. The stretch channel conductance is 10 (a), 15 (b), 20 (c), 25 (d) μS/μF, respectively. The degree of diastolic depolarization (more...)

Changes in APD

The effects of mechanical stretch on the action potential duration (APD) of the heart have been studied in various levels (in situ heart, isolated whole heart, single cardiomyocytes etc.) in many species. In the studies on in situ heart using the contact electrode technique, there are many evidences that the mechanical stretch shortens the monophasic action potential duration [15, 22, 23, 26, 69, 70].

In case of isolated hearts, the effect of stretch on the APD is more complicated. Franz et al. [26] observed a decrease in APD measured at 20 % repolarization and an increase in APD measured at 90 % repolarization level in isolated canine hearts. Calkins et al. [16], however, reported that the mechanical stretch using ventricular inflation shortened the action potential amplitude by only 3 ms (160 to 157 ms for fast, and 216 to 213 ms for slow aortic occlusion) in isolated canine hearts. Nazir and Lab [55] observed a decrease in the duration from 62.55 to 51.95 ms measured at 50 % repolarization and an increase in the duration from 122.45 to 140 ms at 90 % repolarization in isolated guinea-pig hearts. Tavi et al. [71] also observed a similar result with that of Nazir and Lab [55]; the duration of the AP was decreased at positive voltages (APD at 15 % repolarization level) and increased at negative voltages (APD at 90 % repolarization level). Using an optical mapping study, Sung et al. [68] observed no significant change in APD measured at 20 % repolarization but an increase in APD measured at 80 % repolarization level in isolated rabbit hearts.

In case of isolated muscle strip, Lab [47] observed a decrease in APD in isolated frog ventricular muscle strip by stretch. He suggested that an increase in extracellular potassium might be associated with the acceleration of repolarization since clefts and spaces in cardiac muscle are small enough to influence the potassium concentration under certain conditions.

The results of axial stretch on the single cardiomyocytes are variable. White et al. [76] reported that the stretch of single guinea-pig ventricular myocytes produced an action potential shortening. Tung and Zou [73] also observed a decrease in APD in frog ventricular myocytes. Belus and White [6] found that there is a prolongation of the action potential duration at all stages of the plateau and repolarization in single guinea-pig ventricular myocytes to the axial stretch. They proposed that the discrepancy of APD changes to the axial stretch between several studies lies in the level of Ca2+ buffering. Actually, they found that the stretch in the presence of BAPTA shortens the action potential duration, whereas stretch with no added Ca2+ buffer lengthens the action potential duration. With these observations, they proposed that Ca2+ modulation plays a major role in the electrical response of cardiac muscle to a stretch. Zeng et al. [78] found an increase in APD measured at 90 % repolarization level in rat ventricular myocytes. Kamkin et al. [39] found a decrease in the duration at early plateau phase and an increase at the late repolarization in the human and guinea-pig hearts. Zhang et al. [79] also observed similar results (see Fig. 3) with those by Kamkin et al. [39]. Riemer and Tung [59] observed only 4 cases showing the increase in APD out of 350 trials in frog ventricular myocytes; in most cases, there was no significant change in the APD by stretch.

In most cases, the lengthening or shortening effect of the mechanical stretch on the APD was dependent on the level of repolarization. If one measured APD at early repolarization, the response to a stretch was mostly recognized as a decrease in APD. On the other hand, if one measured the APD at late repolarization, the response was recognized as an increase. The involvement of SACs has been suggested to explain the differential effect of mechanical stretch on the APD [14, 19]. As shown in Fig. 2, the reversal potential of the ISAC (ERev, SAC) is close to 0 mV, which is far positive to the resting membrane potential of cardiomyocytes. The activation of SACs, therefore, will generate inward currents at potentials negative to ERev, SAC and outward currents at potentials positive to ERev, SAC. The increase of outward currents at potentials positive to ERev, SAC is thought to shorten the AP, whereas the increase of inward currents at potentials negative to ERev, SAC will make the AP lengthen. As an alternative mechanism of AP lengthening at late repolarization, the appearance of afterdepolarization could be proposed. Franz et al. [26] observed a decrease in the plateau duration of AP in canine hearts by transient occlusions of the ascending aorta. They also observed a small "humps" or early afterdepolarization occurred at the end of phase 3 repolarization, which makes the APD at 90 % repolarization increase. They explained that the increase in APD at 90 % repolarization is due to the development of an afterdepolarization. Stacy et al. [66] proposed that the afterdepolarization might be generated indirectly by a length-dependent rise in [Ca2+]i via the activation of an electrogenic Na+-Ca2+ exchanger. In support of this possibility, Tavi et al. [71] suggested the Na+-Ca2+ exchanger to have a key role in the lengthening of the AP at 90 % repolarization level.

Fig. 5 demonstrates the model-predicted changes in AP and accompanying changes in Na+-Ca2+ exchanger current. It clearly demonstrates the lengthening of AP and the associated increase in the amplitude Na+-Ca2+ exchanger current during a stretch. The shortening of the AP at early repolarization is also notable.

Figure 5. Model-predicted changes in AP shape (upper panel) and Na+-Ca2+ exchanger current (lower panel) during a mechanical stretch (solid line: control; dotted line: stretch).

Figure 5

Model-predicted changes in AP shape (upper panel) and Na+-Ca2+ exchanger current (lower panel) during a mechanical stretch (solid line: control; dotted line: stretch). The stretch channel conductance is 0 μS/μF in control and 25 μS/μF (more...)

Changes in [Ca2+]i with stretch

Resting [Ca2+]i

There are evidences that the mechanical stretch elevates the resting Ca2+ level of cardiomyocytes. Allen et al. [1] suggested that the muscle length influences the resting [Ca2+]i possibly via the SACs and this in turn affects the Ca2+ transients and develops a tension. However, the effect of muscle length on the resting [Ca2+]i, in contrast to the systolic [Ca2+]i, was not clear because the Ca2+-sensitive dye (aequorin) they used was not so sensitive to the resting [Ca2+]i. Using a more sensitive Ca2+ dye (Indo-1 AM), Le Guennec et al. [51], were able to identify an increase in resting [Ca2+]i of guinea-pig ventricular myocytes stretched by carbon fibres. Other studies also demonstrated a clear increase in resting [Ca2+]i [76, 67, 30, 29].

There are also evidences that the mechanical stretch does not elevate the resting [Ca2+]i in rat ventricular myocytes [3, 36, 41] using fura-2 and in rat atrium [71] using Indo-1 AM as a Ca2+ indicator, respectively. Tavi et al. [71] suggested that small changes in resting [Ca2+]i might be hard to detect with the Ca2+ indicaters they used. Alvarez et al. [3] observed no change and even a small decrease in resting [Ca2+]i after an immediate stretch of rat ventricular trabeculae. They proposed that the decrease is consistent with an increase in Ca2+ binding to the troponin C occurring during the fast response to the stretch [35]. Kentish and Wrzosek [41] suggested that slow responses do not require an increase in resting [Ca2+]i, instead they proposed other mediators such as cAMP and inositol triphosphate to be associated with the slow responses. It is also tempting to explain that these contradictory data in the literatures arise from the different balance between the Ca2+ influx and Ca2+ buffering capacity. A moderate or weak increase in Ca2+ influx might be well buffered by SR Ca2+ pump and plasmalemmal Na+-Ca2+ exchanger, whereas a severe increase in Ca2+ influx might eventually exceed the buffering capacity and lead to Ca2+ accumulation in the resting state. The exact influence and role of stretch on the resting [Ca2+]i remain to be studied.

Ca2+ transients

Parmley and Chuck [57] found that the stretch of cat papillary muscles shows a rapid increase in isometric force and a slow secondary increase over the subsequent 10 min of stretch. The rapid response is generally believed to arise from an increase in myofilament Ca2+ sensitivity dependent on the length [41] or crossbridge formation [13, 34]. Slow responses were also observed in whole hearts [72] and in single ventricular myocytes [75]. Allen and Kurihara [2] ascribed the slow response to a slow increase in the amplitude of Ca2+ transients after an increase in muscle length. The increase in the amplitude of Ca2+ transients by mechanical stretch has been clearly demonstrated in rat atrium [71] and in isolated rat ventricular trabeculae [41, 3]. However the mechanism of the increase in the amplitude of Ca2+ transients still remains to be explained. We will now briefly check up some candidate mechanisms responsible for the increase in the amplitude of Ca2+ transients (see Calaghan et al. [13, 14] for thorough review for this issue).

Ca2+ entry by L-type Ca2+ current

The major pathway of Ca2+ entry during an AP in cardiomyocytes is believed to be the L-type Ca2+ current (ICa,L). However there are several studies that the uniaxial stretch does not affect ICa,L in single cardiomyocytes [6, 36, 63, 75]. Kamkin et al. [39, 40] observed even an inhibition of ICa,L by uniaxial stretch using glass stylus. They ascribed this inhibition to the intracellular accumulation of Ca2+ due to the Ca2+ influx through SACs since it was prevented by BAPTA in the cells. In contrast, Matsuda et al. [52] reported that both osmotic cell swelling and inflation enhanced ICa,L in rabbit atrial cells and sinoatrial node cells. It could be summarized that the uniaxial stretch does not enhance the ICa,L, while cell swelling or inflation does. Even though there might be no significant change in ICa,L by uniaxial stretch in a voltage-clamp experiment, there is still a possibility that extra Ca2+ enters the cell via ICa,L during a prolonged depolarization of the AP due to delayed voltage-dependent inactivation and partly contribute to the increase in the amplitude of Ca2+ transients [13, 40].

Ca2+ entry by SACs

There are several studies reporting the Ca2+ permeability as well as Na+ and K+ in SACs of tissue-cultured embryonic chick cardiac myocytes [12, 60, 64] and rat atrial cells [43]. Given the Ca2+ permeability of SACs, it is suggested that the mechanical stretch could increase the amplitude of Ca2+ transients via the activation of SACs [29, 64]. Fig. 6 illustrates the effect of mechanical stretch on the amplitude of Ca2+ transients with different ionic permeability in a model prediction. Interestingly, a removal of Ca2+ still induced a large increase in the amplitude of Ca2+ transients suggesting that some other pathways are probably related to the rise of Ca2+ transients in addition to the Ca2+-conducting SACs.

Figure 6. Model predictions of changes in Ca2+ transients by activation of SACs with different ionic permeability.

Figure 6

Model predictions of changes in Ca2+ transients by activation of SACs with different ionic permeability. Compared with control, magnitude of Ca2+ transients was markedly increased by activation of SACs (PNa:PK:PCa = 1:1.32:0.7). Activation of SACs still (more...)

Ca2+ entry by Na+-Ca2+ exchanger

Since SACs have permeability for Na+ as well as K+ and Ca2+, it is expected that the activation of SACs could increase [Na+]i in addition to [Ca2+]i.. It is generally believed that an increase in [Na+]i could increase [Ca2+]i via the activation of the reverse-mode Na+-Ca2+ exchangers. There are several studies demonstrating the increase in cytosolic and total Na+ concentration by mechanical stretch in human, mouse and rat ventricular myocytes [3, 4, 38]. Na+ accumulation by activation of SACs has been suggested to accelerate the reverse-mode operation of Na+-Ca2+ exchangers during the rising phase of APs [3, 13, 14, 29, 39, 40, 43]. The reverse-mode activation of Na+-Ca2+ exchangers is then thought to make Ca2+ transients bigger during a stretch. Fig. 7 demonstrates the effect of [Na+]i clamp on the stretch-induced changes in Ca2+ transients. This simulation result shows the importance of [Na+]i in making Ca2+ transients bigger.

Figure 7. Comparison of model-predicted changes in Ca2+ transients among control, stretch without [Na+]i clamp and with [Na+]i clamp ([Na+]i = 5.

Figure 7

Comparison of model-predicted changes in Ca2+ transients among control, stretch without [Na+]i clamp and with [Na+]i clamp ([Na+]i = 5.4 mM). Compared with the result obtained from the condition of without [Na+]i clamp, magnitude of Ca2+ transients was (more...)

Pathophysiological potential

The diastolic depolarization to a threshold eventually triggers an action potential without normal pacing electrical stimulus [26, 27, 66], which has been named as the stretch-induced depolarization or arrhythmia. In ventricle, this ectopic rhythm could produce premature ventricular extrasystoles [26]. An accelerated diastolic depolarization and subsequent increase in spontaneous beating rate by a mechanical stretch was confirmed in isolated spontaneously beating rabbit sinoatrial node cells implying that the same mechanism is working on the chronotropic response of the heart to the stretch in the level of pacemaker [20].

The alterations in APD are also suggested to contribute to an arrhythmogenesis. The early afterdepolarization represented by increase in APD at late repolarization was demonstrated to induce the premature beats and atrial tachyarrhythmias in isolated guinea-pig hearts stretched by a balloon [55]. The development of premature beat and atrial fibrillation has also been demonstrated in the isolated right atrial tissue of rats with chronic MI by microelectrode recordings, where premature action potentials were preceded by occurrence of early afterdepolarizations [39]. The shortening of the APD at early repolarization also contributes to the arrhythmogenesis by shortening the wavelength or refractory period of atrial impulse and thus increasing the number of wavelets [58]. Ca2+ increase during an AP is generally thought to induce an early afterdepolarization via the activation of inward current by Na+-Ca2+ exchanger [66]. It has been postulated that the shortening of refractory period favours the re-entrant activity, which predisposes to the generation of the atrial fibrillation [65]. In addition, the inhomogeneity in the refractory period and conduction properties are thought to play a role in the initiation of re-entry because of the increase in possible unidirectional block of premature impulses [58].

Conclusions and perspectives

In summary, stretch-induced changes in electrical activity and Ca2+ transients are mostly initiated by the activation of SACs with direct mechanical stretch. The activation of SACs makes a diastolic depolarization of cardiomyocytes with their reversal potential close to 0 mV. The activation of SACs shortens the APD at early repolarization, while it prolongs the APD at late repolarization. The prolongation of an APD at late repolarization is additionally associated with the increase of inward current by Na+-Ca2+ exchanger in response to elevated [Ca2+]i during a mechanical stretch. The rise in resting [Ca2+]i and Ca2+ transients is also triggered by activation of SACs, which directly or indirectly elevates [Ca2+]i via the Ca2+ entry through the SACs and reverse-mode Na+-Ca2+ exchanger with increasing [Na+]i. The stretch-induced electrical activity and Ca2+ transients is important in the mechanism of the arrhythmogenesis. Future goals of study are to directly demonstrate the association between the results of single cardiomyocytes by mechanical stretch and the results of whole heart by volume or pressure load. The development of an improved technique to record the SACs more faithfully and the investigation of its modulation is also a challenge.


The model of stretch-induced changes in electrical activity used in this study is based on the Kyoto-Model [53, 62]. The Kyoto-Model was originally developed to fit the experimental findings on the guinea-pig sinoatrial node cells and ventricular myocytes. We had to make some species-specific modification because our experimental findings on the stretch-induced electrical activity are mainly obtained from rat atrial myocytes [77, 79]. The ionic currents through the inward rectifier K+ channel (IK1) and depolarization-activated outward K+ channel (IK,out) were modified to fit the experimental results in rat atrial myocytes. The volume of the cell was adjusted to that of the rat atrial myocytes [79]. Ionic concentrations were also modified to be the same as those used in our experimental work. In order to simulate the stretch-induced effects, we also introduced the terms of SACs and background non-selective cation channels into this model.

SACs in the model

The amplitude of ISAC in rat atrial myocytes can be determined by the following equation with slight modification from the previous model [61]:

Image ch12_youme2.jpg

The SAC is defined as the current density (pA/pF) at each degree of direct stretch. ISAC, max is defined as the current density at maximum stretch without disruption of the seal. ΔL is the percentile change in cell length. ΔL1/2 is the ΔL where the SAC reaches half the amplitude of ISAC, max. The s represents the slope factor describing the stretch sensitivity. Fitting the ISAC–stretch relationship in our previous study [79] to the equation (2) gives the value of 16.9 % and 6.3 % corresponding to ΔL1/2 and s, respectively. Since ISAC, max shows a linear voltage-dependence [79]; the amplitude can be expressed simply as the function of permeability and constant field equations for each ion species without considering the voltage-dependent gating of channels. From the reversal potential (Vrev = -6.1 mV) under a physiological salt solution, it was calculated that the permeability ratio of PNa:PK is 1:1.32. The permeability ratio was then used in the model to calculate fluxes of each cation by activation of the ISAC. The permeability ratio of PNa:PCa (1:0.7) was obtained by fitting the results from Kim [43].

Background non-selective cation channels in the model

Under the whole-cell voltage clamp, replacement of Na+ with NMDG+ significantly reduced the membrane conductance in rat atrial myocytes [77]. This conductance still remained after blocking the time- and voltage-dependent ion channels under the isotonic Na+ condition. Although it showed a non-selective permeability over the various cations, the permeability ratio (PCs:PNa:PLi = 1.49:1:0.70) was different from that (PCs:PNa:PLi = 1.05:1:0.98) of ISAC [79]. This conductance was described in the model as a sum of cation components by their relative permeability ratios.


This work was supported by Korea Research Foundation Grant funded by Korea Government (MOEHRD, Basic Research Promotion Fund) (KRF-2005-003-E00014).

We thank Drs. A. Noma, N. Sarai and S. Matsuoka for introducing the Kyoto-Model to us.


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