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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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Mechanical Modulation of Intracellular Ion Concentrations: Mechanisms and Electrical Consequences

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School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK
*Corresponding author: Ed White, Ph.D, School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK, Phone: +44 (0) 1113 343 4248; Telefax: +44 (0) 113 343 4228, e-mail:

Length-dependent changes in the contractility of cardiac muscle arise as a result of mechanisms that can alter intracellular ion concentrations. The contractile response of the heart to stretch is biphasic. Immediately following stretch there is an increase in the sensitivity of the myofilaments to calcium which changes the timecourse of the intracellular calcium transient. This is followed by a secondary slow force response where contractility increases alongside an increase in the amplitude of the calcium transient, and probably an increase in the intracellular sodium concentration.

Modulation of the intracellular concentration of ions such as sodium and calcium will have consequences for the activity of ion channels and electrogenic exchangers sensitive to these ions. This represents a means, additional to the direct activation of stretch-activated channels, for the mechanical modulation of electrical activity. In this review we will detail the experimental evidence for mechanical modulation of intracellular calcium and sodium, the mechanisms that are thought to cause these changes, and discuss the implications for electrical activity in the heart.

We will also discuss how this information must be viewed in the context of the electrical and mechanical inhomogeneity that exist within the various regions of the left ventricle, and the recent observations that stretch may provoke changes in intracellular ion concentrations within specific areas of single cardiac myocytes, such as the sub-sarcolemmal region.


At the turn of the 20th century, Frank and Starling identified what is perhaps the most famous response of the myocardium to mechanical stimulation – an increase in force production. Their work formed the basis of the Frank-Starling law of the heart, which states that the output of the heart is equal to, and determined by, the amount of blood flowing into the heart [29, 69]. The importance of this response is evident when one considers the increase in stroke volume that occurs during exercise, when there is increased ventricular filling and thus dilation, or stretch, of the ventricles. There is an immediate increased contractile response to increased diastolic filling, followed by another, slower increase in cardiac performance that leads to a decline in end-diastolic volume towards its initial value. This was first observed by von Anrep in 1912 [86]. Although von Anrep suggested that the effect was dependent on catecholamine release from the adrenal glands, it has since been established that the mechanism for the slow response is intrinsic to cardiac muscle.

In this chapter we will begin by describing that changes that occur at the cellular level during the biphasic response to stretch, with particular reference to the modulation of intracellular concentrations of Na+ ([Na+]i) and Ca2+ ([Ca2+]i). Our focus will be the secondary slow response, as this is one of our primary areas of research interest. Changes in intracellular Na+ and Ca2+ have implications not only for contractility, but also for the activity of ion channels and exchangers that are sensitive to these ions. We will discuss the consequences that stretch-induced changes in [Na+]i and [Ca2+]i have for the electrical activity of the heart, and describe the influence that mechanical and electrical inhomogeneity, a property intrinsic to normal hearts, may have on these feedback processes.

The rapid response to stretch

When cardiac muscle is stretched there is an immediate increase in both passive and active force. Active force is maximal at a length referred to as Lmax which equates to a sarcomere spacing of 2.2 – 2.3 μm. Allen & Kurihara [3] have shown that the increase in force seen immediately after stretch is not associated with an increase in the magnitude of the [Ca2+]i transient (see Fig. 1). Instead it is due to an increase in the sensitivity of the myofilaments for Ca2+, as demonstrated by a length-dependant leftward shift in the force-Ca2+ curve and a decrease in the [Ca2+] producing half-maximal activation (e.g. [37]). This increase in myofilament Ca2+ sensitivity is reflected in an increase in the affinity of troponin C (TnC) for Ca2+ [38], and evidence suggests that these changes are mediated by the stretch-dependent increase in force rather than length (for reviews see [2, 16]). This dependence on force rather than length reveals the central role of the force-producing cross-bridge in the Frank-Starling mechanism. In essence the length-tension relationship arises because of an increase in the probability of strong binding cross-bridge formation, and it is further enhanced by positive co-operativity whereby strong binding cross-bridges promote the formation of additional cross-bridges [60]. It has been suggested that the strong-binding cross-bridge actually increases the affinity of TnC for Ca2+ through protein-protein interactions within the thin filament [51].

Figure 1. Rapid changes in the time course of the [Ca2+]i transient by stretch A.

Figure 1

Rapid changes in the time course of the [Ca2+]i transient by stretch A. [Ca2+]i transient (upper traces, measured with aequorin) and active tension (lower traces) in an intact rat trabecula at 100% (L) and 81% (S) of Lmax. Stretch increases tension; there (more...)

Several mechanisms are thought to contribute to the increased probability of cross-bridge formation with increased muscle length. When muscle is stretched, the degree of longitudinal thick and thin filament overlap changes and clearly this has implications for cross-bridge availability (see [33]). Another aspect of muscle geometry that changes with stretch is the lateral spacing of the myofilaments. Evidence has shown that a decrease in radial lattice spacing (which will increase the proximity of the myosin head to the actin filament) increases the sensitivity of the myofilaments to Ca2+ [31, 65]. Although there is no question that there is an inverse linear relationship between lattice spacing and Ca2+ sensitivity (see [32]), doubts have been raised as to its relevance in the physiological range of the length-tension relationship in cardiac muscle [51]. Another candidate mechanism for the length-dependent modulation of Ca2+ sensitivity in the heart involves the giant sarcomeric protein titin [18]. Titin forms a structural link between the thick myosin filament and the Z-line, and also binds the thin filament at the Z-line [84]. Although titin controls lattice spacing by exerting radial effects that bring the myofilaments closer together, titin strain also increases the disorder of the myosin heads within the thick filament; an effect which increases the probability of cross-bridge formation [19].

Whilst the increase in myofilament sensitivity to Ca2+ seen during the Frank Starling mechanism ensures that increased force is produced without a requirement for an increase in [Ca2+]i transient amplitude, the change in TnC affinity for Ca2+ does have consequences for the kinetics of the transient. This has been demonstrated by simultaneous recording of the [Ca2+]i transient and active force in rat trabeculae [3]. Figure 1 illustrates the abbreviation of the time course of the transient seen immediately following an increase in muscle length. Conversely when the preparation was allowed to shorten from a long length, the [Ca2+]i transient was prolonged. These effects were thought to be caused by extra binding (during lengthening) or release (during shortening) of Ca2+ from the myofilaments as TnC affinity for Ca2+ changed.

The slow response to stretch

The slow contractile response to stretch (the Anrep effect) is present in the isolated heart [75], in isolated cardiac muscle [68], and in the single cardiac myocyte [89]. Thus the mechanism underlying the slow force response to stretch is intrinsic to the cardiac cell itself, although it may be modulated by paracrine influences of fibroblasts and endothelial cells in intact myocardium. In recent years it has been established that changes in both [Na+]i and [Ca2+]i play a vital role in the slow response, although the mechanisms that underlie these changes are still under debate.

Changes in intracellular ion concentrations during the slow response

Changes in [Ca2+]i

By contrast to the rapid response, the slow increase in contractility upon stretch has been shown to be caused by a corresponding slow increase in the amplitude of the [Ca2+]i transient. This has been demonstrated in intact ventricular muscle and in the stretched ventricular myocyte [3, 17] (see Fig. 2).

Figure 2. Slow changes in [Ca2+]i and force following stretch in intact ventricular muscle and the single ventricular myocyte.

Figure 2

Slow changes in [Ca2+]i and force following stretch in intact ventricular muscle and the single ventricular myocyte. A - [Ca2+]i (measured using aequorin) and force in a feline papillary muscle held at 82% Lmax and 100% Lmax. Upper traces show slow timebase recordings, (more...)

In atrial muscle, the [Ca2+]i transient also increases during the slow response, although the time course of this is more rapid than in ventricular muscle [82]. Pivotally, it has been shown that changes in [Ca2+]i quantitatively account for the magnitude of the slow response, with no further time-dependent changes in myofilament sensitivity occurring after the rapid response [46]. Consistent with this, no change in the time course of contraction or [Ca2+]i is observed during the slow response to stretch in muscle or cells [40, 39]. Changes in diastolic [Ca2+]i during the slow response appear to be species-dependent. Increased diastolic [Ca2+]i has been seen following stretch in muscle and myocytes from the guinea pig [78, 89], but not the rat [4, 17, 39, 46].

Changes in [Na+]i

In intact cardiac muscle from the rat and cat, increased global [Na+]i has been seen on a similar time scale to slow changes in contractility after stretch [4, 70]. However, for a number of years it was considered that the slow response seen at the level of the myocyte was Na+-independent, as no corresponding increase in [Na+]i was detected in single rat cardiac myocytes [39]. At the time, this differential effect of stretch on [Na+]i in the two preparations was reconciled by the idea that paracrine signalling was responsible for modulation of [Na+]i in muscle (see Section 3.3). However, using sensitive detection methods with high spatial resolution (sodium-green fluorescence and electron probe microanalysis), [Na+]i has been shown to increase at 2–4 min following stretch in single murine ventricular myocytes [41]. The observed increase in [Na+]i was spatially heterogenous, with most Na+ hotspots localised close to the surface membrane. It is possible that increases in sub-sarcolemmal [Na+]i following stretch may not be detected in single cells as a change in bulk cytosolic [Na+]i.

Mechanisms underlying the slow response

The temporal and spatial changes in [Ca2+]i and [Na+]i during the slow response may give some clue as to the mechanisms which are responsible. Early work focused on the mechanisms that increase [Ca2+]i; more recently those that increase [Na+]i have also been considered.

Ca2+ and Na+ entry


In the cardiac cell, the major source of Ca2+ influx is via the L-type Ca2+ current (ICa,L). However, there is no evidence that ICa,L contributes to the slow response. In cardiac muscle, Ca2+ channel antagonists do not abolish the slow response [21, 88], and in axially stretched single myocytes, no increase in ICa,L has been recorded [10, 39, 43, 76]. It has not proved possible to correlate directly changes in ICa,L with contractility during the slow response [39] (see Section 4).


Another potential source of Ca2+ entry during the slow response is via the non-selective cationic stretch-activated channel (SAC). Na+ entry via SACs could also increase [Ca2+]i indirectly via the Na+-Ca2+ exchanger (NCX) (see Section 4). The identity of the SAC channel in vertebrates is unknown but it has recently been suggested that it may be the transient receptor potential channel 1 (TRPC-1) [63]. Non-selective cationic SACs show little time-dependent inactivation and have a high conductance (e.g. [43]), therefore maintained stretch could allow sufficient influx of Ca2+ or Na+ to account for the slow response. Using a mathematical model of the atrial myocyte, Tavi et al. [82] have shown that the slow increase in [Ca2+]i seen upon stretch of rat atrial muscle can be mimicked by introducing a non-selective cationic SAC conductance in parallel with increased TnC affinity for Ca2+. Stretch of human atrial myocytes produces a current consistent with ISAC [44]. In single channel recordings from rat atrial myocytes, however, only K+-selective SACs have been seen; clearly K+-selective SACs would have very different implications for electrical activity and intracellular ion concentrations to the non-selective cationic SAC. The K+-selective SACs have been equated with the mechanosensitive twin pore domain channel TREK 1 [66] (see [20] for a review).

Using ventricular tissue, several studies have relied on streptomycin as a blocker of non-selective cationic SACs (see [9, 10]) to determine the role of these channels in the response to stretch. In murine myocytes, streptomycin abolishes the inward current seen following stretch, as well as the peripheral increase in [Na+]i detected using electron probe microanalysis [49]. Some have found streptomycin to be effective in attenuating the slow force response; others have not. In cardiac muscle and single myocytes from the rat, we have shown that the magnitude of the slow response is significantly reduced by streptomycin ([17], see Fig. 3). Others, however, have found streptomycin to be without significant effect on the slow response in rat and failing human cardiac muscle [56, 88].

Figure 3. The stretch activated channel (SAC) contributes to the slow response to stretch in papillary muscle and ventricular myocytes from the rat.

Figure 3

The stretch activated channel (SAC) contributes to the slow response to stretch in papillary muscle and ventricular myocytes from the rat. A. Streptomycin (STREP; 80 μM) significantly reduces the amplitude of the slow force response in muscles (more...)

As changes in diastolic [Ca2+]i are not seen in rat cardiac muscle during the slow response (Section 3.1), the implication is that increased Ca2+ loading takes place during systole in the rat. Inhibition of reverse-mode NCX has been shown to attenuate the magnitude of the slow force response to stretch in other species (cat, rabbit and failing human myocardium; [70, 87, 88]. A possible scenario that could explain the temporal characteristics of the slow response (see [11]) is that Ca2+ entry occurs secondary to Na+ loading through SACs. Although both ions can permeate the channel, data from human atrial and guinea pig ventricular myocytes suggest that the permeability is less for Ca2+ than Na+ [41, 44].

Na+-H+ exchanger

A body of evidence suggests another source of increased [Na+]i during the slow response, besides ISAC. This is via the Na+-H+ exchanger (NHE). Several groups have shown that NHE inhibition reduces the magnitude of the slow response [17, 70, 87]. We recently demonstrated for the first time that NHE inhibition is effective in both multicellular preparations and in the single cardiac myocyte from the rat [17].

In stretched murine myocytes, global increments in [Ca2+]i (measured by electron probe microanalysis during diastole) were reduced by the NHE inhibitor cariporide [50]. However, these data are not consistent with cariporide acting through NHE inhibition, as increased peripheral [Na+]i (which should act as the stimulus for raised [Ca2+]i ) was not sensitive to cariporide [50].

It is possible that both SACs and the NHE play a role in the slow response, and that the balance of these two mechanisms depends on species and/or the stretch stimulus. Han et al. [35] have shown, using computer modelling, that activation of non-selective cationic SACs and stimulation of NHE have qualitatively similar effects on Ca2+ handling in cardiac cells.

Ca2+ release

In heart muscle the sarcoplasmic reticulum (SR) is the major site of [Ca2+]i release yet, interestingly, most evidence suggests that Ca2+ release from the SR does not underlie the slow response. Inhibition of SR Ca2+ release does not change the relative magnitude of the slow response in rat, rabbit or ferret papillary muscle [11, 39, 45, 46], although it has been shown to reduce the slow response in the intact canine heart and failing human myocardium [88]. However, under conditions when a functional SR is not obligatory for the slow response, the SR does appear to be involved in the handling of the extra [Ca2+]i [11, 46].

In 2001, Vila Petroff et al. [85] proposed a novel mechanism for the slow response which assigned the SR a primary role in this phenomenon. Experiments were performed with rat ventricular myocytes stretched within an agarose gel, and rat trabeculae. These workers proposed that the slow increase in [Ca2+]i transient following stretch was due to activation of the phosphatidyl inositol-3-OH kinase (Ptd-Ins-3-OH kinase) -Akt - endothelial nitric oxide synthase (eNOS) axis which increases ryanodine receptor (RyR) sensitivity via s-nitrosylation. However, in our hands, the slow response is not attenuated by Ptd-Ins-3-OH kinase inhibition in cells or muscle from the rat heart [17], and several studies have shown no reduction of slow response magnitude when NOS is inhibited in muscle from rabbits, rats and patients with heart failure [17, 87, 88]. A small reduction in slow response magnitude with NOS inhibition has been reported by Bardswell & Kentish [7] in rat trabeculae, one of the preparations used by Vila-Petroff et al. [85].

It has proved difficult to reconcile the data of Vila-Petroff et al. with the existing views of the slow response. This is due in part to the large body of evidence that fails to demonstrate a pivotal role of the SR in the slow response. However, another concern is that enhanced RyR activity only results in transient changes in [Ca2+]i and contraction [27]. Thus for the temporal characteristics of the slow response to be fulfilled, there would have to be a concurrent increase in SR Ca2+ loading to compensate for increased SR Ca2+ release.

Mechanotransduction of the slow response

The mechanotransductive pathways that link stretch with the end effectors of the slow response have yet to be described. Are ion channels and exchangers directly activated by tension in the membrane bilayer? Or does this occur via tethering of the proteins to the extracellular matrix or cytoskeleton, or by activation of intracellular signalling cascades? For SACs, it has been suggested that gating is dependent on force transmission from linking elements such as the extracellular matrix or cytoskeleton (see [41, 74], although human TRPC1 (recently proposed as a component of the vertebrate SAC) can be gated directly by tension developed in the bilayer [63].

However, the spatial relationship between stretch and the cellular response suggests that the mechanisms for the slow response are `decentralised' [47]. When cardiac cells are subject to localized stretch (rather than end-to-end stretch) increased peripheral [Na+]i is seen in areas of the myocytes outside those where sarcomere deformation was seen [41]. This propagation of the stretch effect implies the involvement of intracellular signalling cascades. Indeed, the regulatory domain of the NHE has multiple kinase target sites that are known to modify its activity [6, 8]. Early work using cardiac muscle from the rat and cat suggested that protein kinase C (PKC) activates NHE during the slow response following sequential release of angiotensin II (from myocytes) and endothelin 1 (from myocytes or fibroblasts) [4, 70]. This is not a universal finding as activation of NHE during stretch is independent of both angiotensin II and endothelin 1 in rabbit cardiac muscle and the failing human myocardium [88, 89] which suggests a more direct stretch-regulation of exchanger activity.

Despite a decentralised model of signalling for the slow response, some aspects of the stretch-induced signalling pathways are very local; evidence suggests that SACs, NHE and NCX are concentrated in the t-tubular portion of the sarcolemmal membrane [71, 90, 92,] which should provide a very sensitive signalling microenvironment to translate increased subsarcolemmal [Na+]i into increased reverse mode NCX activity. Likewise, the signalling mechanism proposed to increase RyR sensitivity following stretch relies in part on the localisation of its components to the caveolar microdomain [28].

Slow response signalling pathways as a prequel to disease

Maintained myocardial stretch is a trigger for the development of cardiac hypertrophy. Many of the signalling molecules that have been linked with the slow response, including Ca2+, PKC and Ptd-Ins-3-OH kinase, have also been implicated in the development of cardiac hypertrophy (see [73] and [14] for a review). The hypertrophic response has been shown to be attenuated by NHE inhibition, independent of the nature of the hypertrophic stimulus [6]. Although NHE activation has consequences for both [Na+]i and pHi, under physiological conditions the change in pHi is compensated for by bicarbonate-dependent transporters [22]. Therefore stretch-induced increases in [Na+]i (and [Ca2+]i) responsible for the slow response also have the potential to be pro-hypertrophic stimuli.

The effect of changes in ion concentration on electrical activity

In previous sections we have described how changes in TnC affinity for Ca2+ immediately following stretch can modulate the time course of the [Ca2+]i transient, and how the slow response is associated with an increase in the amplitude of the [Ca2+]i transient and the level of [Na+]i. Modulation of [Ca2+]i and [Na+]i can influence the electrical activity of the heart through effects upon dependant channels and exchangers. This can be via effects on ion equilibrium potentials, or through activation (e.g. of IK [83]) or inactivation (e.g. of ICaL [58]) of sensitive channels. The study by Du Bell et al [26] shows the impact of [Ca2+]i on electrical activity by describing the modulation of action potential configuration by the amplitude and time course of the [Ca2+]i transient.

Of the channels and exchangers (other than SACs) that have been implicated in the contractile response of cardiac muscle to stretch, the NCX has perhaps the major role. The exchanger can work in forward (Ca2+ extrusion) or reverse (Ca2+ influx) mode. It is generally accepted that the stoichiometry of NCX is 3:1 (Na+:Ca2+) (e.g. [72]), therefore the exchanger is electrogenic. The direction of Na+, and hence current, flow depends on the reversal potential of the exchanger (ENaCa = 3ENa - 2ECa) and the membrane potential (Em). When Em is negative to ENaCa, Ca2+ is extruded and an inward depolarising current is generated. As both [Ca2+]i and membrane potential change appreciably during the action potential, it is clear that the direction and amplitude of the NCX current will also be subject to change.

Lab et al. [55] showed that the prolongation of the [Ca2+]i transient in response to a quick release from long length was mirrored by a prolongation of the action potential duration (APD). The effect was most prominent when the release was late, rather than early, in the action potential. The explanation offered by the authors was that Ca2+, suddenly released from the myofilaments, as a result of decreased TnC affinity, accumulated in the cytoplasm and was extruded from the cell via NCX, generating an inward current. This interpretation was consistent with the observation that the increase in [Ca2+]i preceded the effect on membrane potential. Computer modelling [42] also supported this explanation of the experimental observation. When considering these findings it is worth noting that the change in length that provoked this alteration in the [Ca2+]i transient and action potential duration was quite large, (`isotonic' shortening from Lmax). Other modelling studies have described how stretch-induced changes in myofilament Ca2+ sensitivity can modulate the [Ca2+]i transient and thereby the profile of the action potential [48]. Experimentally, further evidence that Ca2+ may influence the electrical response to stretch has been provided by Han et al. [34] who showed that stretch prolongation of APD in rat atrial preparations was abolished by reducing [Ca2+]i transient magnitude by SR inhibition.

However, some evidence argues against a powerful role for myofilament modulation of Ca2+ binding in the electrical response to stretch. It was observed [30, 36] that, in the canine heart, changing from isovolumic to an ejecting mode of contraction (i.e. allowing a greater degree of shortening and subsequent re-lengthening) depressed the late depolarisations of the ventricular monophasic action potential. These studies suggest that muscle shortening associated with ejection causes the inactivation of depolarising cationic SACs rather than the activation of depolarising Ca2+-dependant currents.

One technical difficulty that confounds the assessment of the effect of Ca2+ on stretch-activated electrical events is the use of Ca2+ buffers in the recording pipettes of whole-cell patch-clamp studies. These buffers are often required to stabilise recordings under the difficult conditions imposed by stretching. We attempted to circumvent this problem by using the carbon fibre technique to stretch single guinea pig ventricular myocytes whilst simultaneously recording electrical activity using microelectrodes (Fig. 4, and [10]). One carbon fibre was used to protect the site of the microelectrode impalement. The use of sharp microelectrodes avoided the necessity for Ca2+ buffers in the electrode solution, however, as the resistance of these electrodes is too high to use the conventional continuous voltage clamp technique, discontinuous `switch' voltage clamp was used.

Figure 4. Simultaneous stretching of a guinea pig ventricular myocyte and recording of electrical activity.

Figure 4

Simultaneous stretching of a guinea pig ventricular myocyte and recording of electrical activity. The microelectrode is used to record membrane potential or currents. It is placed behind the stiff fibre to protect the site of impalement during stretch. (more...)

Recordings were made within 2 min of stretch and we observed that stretch prolonged the APD. The increase in APD with stretch was abolished by application of the cationic SAC blocker streptomycin at 40 μM. Although streptomycin can reduce other currents such as ICa,L at higher concentrations [9], we have shown that 50 μM streptomycin does not alter the APD or [Ca2+]i transients of unstretched myocytes [10]. The effect of streptomycin on stretch-induced prolongation of the action potential suggests a role for SACs in the response to stretch. Indeed under action potential clamp (where the cell is voltage clamped with its own action potential waveform [25], stretch evoked a streptomycin-sensitive current consistent with the activation of non-selective cationic SACs (Fig. 5).

Figure 5. Stretch-activated membrane currents in guinea pig ventricular myocytes recorded by action potential clamp.

Figure 5

Stretch-activated membrane currents in guinea pig ventricular myocytes recorded by action potential clamp. A. Mean current–voltage relationship for the stretch-activated current from 10 cells, having a current of greater than 5 pA at +30 mV. Stretch increased (more...)

However the effect of stretch on the action potential was also abolished by exposure to 5 μM BAPTA-AM, a cell permeant Ca2+ buffer that reduces the [Ca2+]i transient to such an extent that contraction is abolished (Fig. 6).

Figure 6. Comparison of the effects of stretch on the action potential of guinea pig ventricular myocytes in the presence and absence of streptomycin or intracellular calcium buffering with BAPTA.

Figure 6

Comparison of the effects of stretch on the action potential of guinea pig ventricular myocytes in the presence and absence of streptomycin or intracellular calcium buffering with BAPTA. The upper panel shows representative experimental records of action (more...)

These data lead us to conclude that both SACs and [Ca2+]i are important for the response of single myocytes to stretch. Consistent with a role for [Ca2+]i in the effects of stretch on the action potential, in studies with single guinea pig ventricular myocytes at 37°C, the consequences of stretch are dependent upon the level of [Ca2+]i buffering used: with 5 mM EGTA, an APD shortening with stretch [61]; with 10 μM EGTA, early shortening and late lengthening of the APD [43]; with no exogenous buffering we saw APD lengthening converted to a non-significant shortening with 5μM BAPTA-AM [10].

However, it is difficult to characterise the effects of stretch across preparations and species, and stretch-dependent mechanisms are still proving elusive. For example, Sung et al. [81] showed a stretch-induced lengthening of the epicardial APD in rabbit Langendorff-perfused hearts, measured by optical mapping with the voltage sensitive dye di-4-ANEPPS. Interestingly, in order to reduce motion errors associated with this technique, the cross-bridge uncoupler BDM was used. BDM has been shown to abolish the release of extra Ca2+ associated with the shortening-induced fall in myofilament Ca2+ sensitivity [53], suggesting that the influence of this mechanism in the responses seen in [81] was small. Sung et al. also showed that the effect of load on the APD was resistant to streptomycin. These data are quite different to those obtained in stretched myocytes in which APD prolongation was seen but was sensitive to both [Ca2+]i manipulation and streptomycin [10].

The increase in the amplitude of the [Ca2+]i transient that occurs during the slow increase in force might influence electrical activity. In a study performed in feline papillary muscles, Allen [1] observed that stretch caused initial APD shortening, followed by a slow lengthening of APD. Tavi et al. [82] also report a slow increase in pressure and a lengthening of the APD with sustained atrial stretch. Action potential prolongation could allow extra Ca2+ to enter via ICa,L due to delayed voltage-dependent inactivation. In support of a role for APD in the slow response, Hongo et al. [39] failed to see a slow contractile response to stretch in single rat myocytes that were voltage clamped (and subjected to a fixed duration of depolarisation).

However, there are arguments against a role for increased APD in the slow force response to stretch. Von Lewinski et al. [88] failed to see APD prolongation in rabbit ventricular muscle after stretch. A secondary increase in ICa,L during the maintained plateau of the action potential as a mechanism for the slow response is not consistent with the lack of effect of Ca2+ channel antagonists in cardiac muscle (see Section 3.2.1). Furthermore, if [Na+]i influx is the trigger for the secondary slow increase in [Ca2+]i, as evidence suggests (Section 3.2.1), the electrical consequences of this will be a shortening of APD due to activation of outward (Na+-extruding) NCX current.

The influence of mechanical and electrical inhomogeneity

Cellular inhomogeneities

So far, stretch-dependent mechanisms have been discussed in terms of `generic' cardiac muscle. However it is evident that there are differences in the mechanical stimuli and properties of cardiac muscle from different regions of the heart e.g. atria and ventricle, left heart and right heart. What is less well appreciated, but of equal importance to the function and dysfunction of the heart, are the inhomogeneities in stimuli and properties within the left ventricle. Wall stress [67] and strain [64, 79] vary across the thickness of the ventricular wall, as does the orientation of the ventricular muscle sheets [80, 13]. These sheets, which can be just a few myocytes thick, are bounded by connective tissue and shear against each other during the wringing action of systolic ejection [59, 79]. The timing of myocyte lengthening and shortening through a single cardiac cycle is also thought to vary across the wall [79]. Thus the type, degree and timing of mechanical stimuli delivered to, for example, a sub-endocardial myocyte and a sub-epicardial myocyte might be very different. This has implications for both the [Ca2+]i transient (because of Ca2+-dependent currents) and the action potential (as membrane potential is a major determinant of the driving force for ion movement). Indeed, as we have already discussed (Section 4), the timing of a stretch or release does influence its electrical outcome (e.g. [91, 55]). However, the situation is further complicated because there are also regional differences in the intrinsic properties of myocytes. For example, sub-endocardial myocytes are typically reported to have longer action potentials and a greater affinity for Ca2+ than sub-epicardial myocytes [5, 24]. The overall effect that myocardial shearing, stretching and shortening during the cardiac cycle has on the binding and release of Ca2+ from the myofilaments (and as a consequence the free [Ca2+]i and dependent ionic currents), and on the activation of SACs, will be influenced by these regional differences.

Sub-cellular inhomogeneities

When considering the effects of ion concentrations upon sarcolemmal ion channels and exchangers, it is now apparent that it is the sub-sarcolemmal concentration of these ions that will influence membrane current and exchanger activity. The concentration of Ca2+ and Na+ in the sub-sarcolemmal `fuzzy-space' is different to that in the cytosolic compartment [57]. Furthermore, there is evidence that stretch can produce local increases in [Na+]i and [Ca2+]i, for example, sub-sarcolemmal [Ca2+]i in chick cardiac myocytes in response to gentle prodding [77] and peripheral [Na+]i in stretched murine ventricular myocytes [41, 49, 50]. By implication, [Ca2+]i increases in the region of the ryanodine receptor (as evidenced by changes in Ca2+ spark properties) in rat ventricular myocytes stretched within a gel matrix [85].

Within the myocyte itself, there is increasing evidence that channels and exchangers are not uniformly distributed in the sarcolemma, but are grouped in specific regions such as the t-tubules [23]. The effect that stretch has on t-tubules is not well understood, and the stimulus presented to them by axial stretch may be different to that in the surface sarcolemma, because of their orientation and their association with the sarcomeric Z-lines [52]. However the observation that atrial myocytes, which lack a highly developed tubular system, respond both electrically and mechanically in a similar way to ventricular myocytes may be an indication that the t-tubule is not a major player in the slow response (although the t-tubule may increase the efficiency of stretch-dependent NCX activation, see Section 3.3).

In line with this hypothesis, we have observed that de-tubulation of ventricular myocytes (using formamide, [15]) has little effect on the magnitude of the response to mechanical stimulation by osmotic swelling, although it does slow the time-course of the response ([62], Fig. 7). The conclusion to this study is that de-tubulation reduces the surface area for water influx, but that the channels responsible for regulating the volume response are not exclusively located in the t-tubules.

Figure 7. Changes in cell volume (mean ± S.

Figure 7

Changes in cell volume (mean ± S.E.M) relative to pre-swollen volume in response to hypo-osmotic solution (HYPO) in control (•) and detubulated (○) myocytes. Hypo-osmotic solution (191 ± 1 mosM) was iso-ionic with the control (more...)

Conclusions and perspectives

Mechanical stimulation has many consequences for the heart. In this chapter we have described changes in [Na+]i and [Ca2+]i, in electrical activity, and in force that occur following myocardial stretch. Mechanical stretch can have `direct' effects on electrical activity via stretch-sensitive ion channels, mediated through increased bilayer tension or by cytoskeletal tethering. However, there is a more subtle aspect to mechano-electric feedback which is associated with the length-dependent modulation of [Na+]i and [Ca2+]i. Changes in the intracellular concentration of these ions can regulate the activity of certain ion channels and electrogenic exchangers, with consequences for electrical activity. In order to understand the full implications of these effects, the mechanisms associated with the rapid and slow increase in force, and the degree, timing and cellular location of the changes in ion concentrations that they cause, need to be better understood. Of equal importance is an understanding of why diverse experimental findings are reported from apparently similar studies. At the heart of the problem may be our current inability to measure accurately the stimuli associated with myocardial stretch.


The authors thank the British Heart Foundation for funding our work.


Allen DG. On the relationship between action potential duration and tension in cat papillary muscle. Cardiovasc Res. (1977);11:210–21. [PubMed: 872160]
Allen DG, Kentish JC. The cellular basis of the length-tension relation in cardiac muscle. J Mol Cell Cardiol. (1985);17:821–840. [PubMed: 3900426]
Allen DG, Kurihara S. The effects of muscle length on intracellular calcium transients in mammalian cardiac muscle. J Physiol. (1982);327:79–94. [PMC free article: PMC1225098] [PubMed: 7120151]
Alvarez BV, Perez NG, Ennis IL, Camilion de Hurtado MC, 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. (1999);85:716–722. [PubMed: 10521245]
Antzelevitch C, Fish J. Electrical heterogeneity within the ventricular wall. Basic Res Cardiol. (2001);96:517–527. [PubMed: 11770069]
Avkiran M, Haworth RS. Regulatory effects of G-protein coupled receptors on cardiac sarcolemmal Na/H exchanger activity: signalling and significance. Cardiovasc Res. (2003);57:942–952. [PubMed: 12650872]
Bardswell S, Kentish J. A role for NO in the slow force response to a length change in cardiac muscle. J Physiol. (2004);557P:PC6.
Baumgartner M, Patel H, Barber DL. Na+/H+ exchanger NHE1 as plasma membrane scaffold in the assembly of signaling complexes. Am J Physiol. (2004);287:C844–C850. [PubMed: 15355855]
Belus A, White E. Effects of streptomycin sulphate on ICaL, IKr and IKs in guinea-pig ventricular myocytes. Eur J Pharmacol. (2002);445:171–178. [PubMed: 12079681]
Belus A, White E. Streptomycin and intracellular calcium modulate the response of single guinea pig ventricular myocytes to axial stretch. J Physiol. (2003);546:501–509. [PMC free article: PMC2342506] [PubMed: 12527736]
Bluhm WF, Lew WYW. Sarcoplasmic reticulum in cardiac length-dependent activation in rabbits. Am J Physiol. (1995);269:H965–H972. [PubMed: 7573541]
Bluhm WF, Lew WY, Garfinkel A, McCulloch AD. Mechanisms of length history-dependent tension in an ionic model of the cardiac myocyte. Am J Physiol. (1998);274:H1032–H1040. [PubMed: 9530218]
Bovendeerd PH, Huyghe JM, Arts T, van Campen DH, Reneman RS. Influence of endocardial-epicardial crossover of muscle fibers on left ventricular wall mechanics. J Biomech. (1994);27:941–51. [PubMed: 8063844]
Brancaccio M, Fratta L, Notte A, Hirsch E, Poulet R, Guazzone S, De Acetis M, Vecchione C, Marino G, Altruda F, Silengo L, Tarone G, Lembo G. Melusin, a muscle-specific integrin β1-interacting protein, is required to prevent cardiac failure in response to chronic pressure overload. Nat Med. (2003);9:68–75. [PubMed: 12496958]
Brette F, Komukai K, Orchard CH. Validation of formamide as a detubulation agent in isolated rat cardiac cells. Am J Physiol. (2002);283:H1720–H1728. [PubMed: 12234828]
Calaghan SC, White E. The role of calcium in the response of cardiac muscle to stretch. Prog Biophys Mol Biol. (1999);71:59–90. [PubMed: 10070212]
Calaghan S, White E. Activation of Na+/H+ exchange and stretch activated channels underlies the slow inotropic response to stretch in myocytes and muscle from the rat heart. J Physiol. (2004);559:205–214. [PMC free article: PMC1665066] [PubMed: 15235080]
Cazorla O, Vassort G, Garnier D, Le Guennec J-Y. Length modulation of active force in rat cardiac myocytes: is titin the sensor? J Mol Cell Cardiol. (1999);31:1215–1227. [PubMed: 10371696]
Cazorla O, Wu Y, Irving TC, Granzier H. Titin-based modulation of calcium sensitivity of active tension in mouse skinned cardiac myocytes. Circ Res. (2001);88:1028–1035. [PubMed: 11375272]
Chemin J, Patel AJ, Duprat F, Lauritzen I, Lazdunski M, Honore E. A phospholipid sensor controls mechanogating of the K+ channel TREK-1. EMBO J. (2005);24:44–53. [PMC free article: PMC544907] [PubMed: 15577940]
Chuck L, Parmley CC. Caffeine reversal of the length-dependent changes in myocardial state in the cat. Circ Res. (1980);47:592–598. [PubMed: 7408135]
Cingolani HE, Camilion de Hurtado MCC. Na-H exchanger inhibition. A new anti-hypertensive tool. Circ Res. (2002);90:751–753. [PubMed: 11964365]
Despa S, Brette F, Orchard CH, Bers DM. Na/Ca exchange and Na/K-ATPase function are equally concentrated in transverse tubules of rat ventricular myocytes. Biphys J. (2003);85:3388–3396. [PMC free article: PMC1303616] [PubMed: 14581240]
Diffee GM, Nagle DF. Regional differences in effects of exercise training on contractile and biochemical properties of rat cardiac myocytes. J Appl Physiol. (2003);95:35–42. [PubMed: 12547843]
Doerr T, Denger A, Trautwein W. Calcium currents in single SA nodal cells of the rabbit heart studied with action potential clamp. Pflügers Arch. (1989);413:599–603. [PubMed: 2726423]
Du Bell WH, Boyett, MR, Spurgeon, HA, Talo, A, Stern MD, Lakatta EG. The cytosolic calcium transient modulates the action potential of rat ventricular myocytes. J Physiol. (1991);436:347–369. [PMC free article: PMC1181509] [PubMed: 2061836]
Eisner DA, Trafford AW. No Role for the Ryanodine Receptor in Regulating Cardiac Contraction? News Physiol Sci. (2000);15:275–279. [PubMed: 11390926]
Feron O, Belhassen L, Kobzik L, Smith TW, Kelly RA, Michel T. Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J Biol Chem. (1996);271:22810–2284. [PubMed: 8798458]
Frank O. Zur dynamik des herzmusckels. Z Biol. (1895);32:370–447.
Franz MR, Burkhoff D, Yue DT, Sagawa K. Mechanically induced action potential changes and arrhythmia in isolated and in situ canine hearts. Cardiovas Res. (1989);23:213–231. [PubMed: 2590905]
Fuchs F, Wang Y-P. Sarcomere length versus interfilament spacing as determinants of cardiac myofilament Ca2+ sensitivity and Ca2+ binding. J Mol Cell Cardiol. (1996);28:1375–1383. [PubMed: 8841926]
Fukuda N, Wu Y, Farman G, Irving TC, Granzier H. Titin-based modulation of active tension and interfilament lattice spacing in skinned rat cardiac muscle. Pflügers Arch. (2005);449:449–457. [PubMed: 15688246]
Gordon AM, Huxley AF, Julian FJ. The variation in isometric tension with sarcomere length in vertebrate muscle fibres. J Physiol. (1966);184:170–192. [PMC free article: PMC1357553] [PubMed: 5921536]
Han C, Tavi P, Weckstrom M. Role of the sarcoplasmic reticulum in the modulation of rat cardiac action potential by stretch. Acta Physiol Scand. (1999);167:111–117. [PubMed: 10571546]
Han C, Tavi P, Weckstrom M. Modulation of action potential by [Ca2+]i in modelled rat atrial and guinea-pig ventricular myocytes. Am J Physiol. (2002);282:H1047–H1054. [PubMed: 11834503]
Hansen DE. Mechanoelectric feedback effects of altered preload, afterload, and ventricular shortening. Am J Physiol. (1993);264:H423–H432. [PubMed: 8447458]
Hibberd MC, Jewell BR. Calcium and length-dependent force production in rat ventricular muscle. J Physiol. (1982);329:527–540. [PMC free article: PMC1224794] [PubMed: 7143258]
Hofmann PA, Fuchs F. Effect of length and cross-bridge attachment on Ca2+ binding to cardiac troponin C. Am J Physiol. (1987);253:C90–C96. [PubMed: 2955701]
Hongo K, White E, Le Guennec J-Y, Orchard CH. Changes in [Ca2+]i, [Na+]i and Ca2+ current in isolated rat ventricular myocytes following an increase in cell length. J Physiol. (1996);491:599–609. [PMC free article: PMC1158804] [PubMed: 8815197]
Hongo K, White E, Orchard CH. The effect of stretch on contraction and the Ca2+ transient in ferret ventricular muscles during acidosis and hypoxia. Am J Physiol. (1995);269:C690–C697. [PubMed: 7573399]
Isenberg G, Kazanski V, Kondratev D, Gallitelli MF, Kiseleva I, Kamkin A. Differential effects of stretch and compression on membrane currents and [Na+]c in ventricular myocytes. Prog Biophys Mol Biol. (2003);82:43–56. [PubMed: 12732267]
Janvier NC, Boyett MR. The role of Na-Ca exchange current in the cardiac action potential. Cardiovasc Res. (1996);32:69–84. [PubMed: 8776405]
Kamkin A, Kiseleva I, Isenberg G. Stretch-activated currents in ventricular myocytes: amplitudes and arrhythmogenesis effect increase with hypertrophy. Cardiovasc Res. (2000);48:409–420. [PubMed: 11090836]
Kamkin A, Kiseleva I, Wagner KD, Bohm J, Theres H, Gunther J, Scholz H. Characterization of stretch-activated ion currents in isolated atrial myocytes from human hearts. Pflügers Arch. (2003);446:339–346. [PubMed: 12799902]
Kentish JC, Davey R, Largen P. Isoprenaline reverses the slow force responses to a length change in isolated rabbit papillary muscle. Pflügers Archiv. (1992);421:519–521. [PubMed: 1334258]
Kentish JC, Wrzosek A. Changes in force and cytosolic Ca2+ concentration after length changes in isolated rat ventricular trabeculae. J Physiol. (1998);506:431–444. [PMC free article: PMC2230716] [PubMed: 9490870]
Knöll R, Hoshijima M, Chien K. Cardiac mechanotransduction and implications for heart disease. J Mol Med. (2003);81:750–756. [PubMed: 14551702]
Kohl P, Day K, Noble D. Cellular mechanisms of cardiac mechano-electric feedback in a mathematical model. Can J Cardiol. (1998);14:111–119. [PubMed: 9487283]
Kondratev D, Gallitelli MF. Increments in the concentrations of sodium and calcium in cell compartments of stretched mouse ventricular myocytes. Cell Calcium. (2003);34:193–203. [PubMed: 12810062]
Kondratev D, Christ A, Gallitelli MF. Inhibition of the Na+-H+ exchanger with cariporide abolishes stretch-induced calcium but not sodium accumulation in mouse ventricular myocytes. Cell Calcium. (2005);37:69–80. [PubMed: 15541465]
Konhilas JP, Irving TC, de Tombe PP. Myofilament calcium sensitivity in skinned rat cardiac trabeculae: role of interfilament spacing. Circ Res. (2002);90:59–65. [PubMed: 11786519]
Kostin S, Scholz D, Shimada T, Maeno Y, Mollnau H, Hein S, Schaper J. The internal and external protein scaffold of the T-tubular system in cardiomyocytes. Cell Tissue Res. (1998);294:449–460. [PubMed: 9799462]
Kurihara S, Saeki Y, Hongo K, Tanaka E, Sudo N. Effects of length change on intracellular Ca2+ transients in ferret ventricular muscle treated with 2,3-butanedione monoxime (BDM) Jpn J Physiol. (1990);40:915–920. [PubMed: 2094785]
Kostin S, Scholz D, Shimada T, Maeno Y, Mollnau H, Hein S, Schaper J. The internal and external protein scaffold of the T-tubular system in cardiomyocytes. Cell Tissue Res. (1998);294:449–460. [PubMed: 9799462]
Lab M, Allen D, Orchard CH. The effect of shortening on myoplasmic calcium concentration and on action potential in mammalian ventricular muscle. Circ Res. (1984);55:825–29. [PubMed: 6499137]
Lamberts RR, Van Rijen MH, Sipkema P, Fransen P, Sys SU, Westerhof N. Coronary perfusion and muscle lengthening increase cardiac contraction: different stretch-triggered mechanisms. Am J Physiol. (2002);283:H1515–H1522. [PubMed: 12234804]
Leblanc N, Hume JR. Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum. Science. (1990);248:372–376. [PubMed: 2158146]
Lee KS, Marban E, Tsien RW. Inactivation of calcium channels in mammalian heart cells: joint dependence on membrane potential and intracellular calcium. J Physiol. (1985);364:395–411. [PMC free article: PMC1192977] [PubMed: 2411919]
Le Grice IJ, Smaill, BH, Chai LZ, Edgar SG, Gavin JB, Hunter PJ. Laminar structure of the heart: ventricular arrangement and connective tissue architecture in the dog. Am J Physiol. (1995);269:H571–H582. [PubMed: 7653621]
Lehrer SS, Geeves MA. The muscle thin filament as a classical cooperative/allosteric regulatory system. J Mol Biol. (1998);277:1081–1089. [PubMed: 9571024]
Lei M, Camelliti P, Cooper P, Linz K, Kohl P. Stretch-activated whole-cell currents during the action potential of guinea pig ventricular myocytes. J Physiol. (2001);533P:40P.
Lovett J, Calaghan SC, White E. Effect of actin disruption and de-t-tubulation on the volume response of adult rat ventricular myocytes to hypo-osmotic challenge. J Physiol. (2003);551P:PC1.
Maroto R, Raso A, Wood TG, Kurosky A, Martinac B, Hamill OP. TRPC1 forms the stretch-activated cation channel in vertebrate cells. Nat Cell Biol. (2005);7:179–185. [PubMed: 15665854]
Mazhari R, Omens JH, Pavelec BS, Covel JW, McColloch AD. Transmural distribution of three-dimensional systolic strains in stunned myocardium. Circ. (2001);104:336–341. [PubMed: 11457754]
McDonald KS, Moss RL. Osmotic compression of single cardiac myocytes eliminates the reduction in Ca2+ sensitivity of tension at short length. Circ Res. (1995);77:115–119. [PubMed: 7788878]
Niu W, Sachs F. Dynamic properties of stretch-activated K+ channels in adult rat atrial myocytes. Prog Biophys Mol Biol. (2003);82:121–135. [PubMed: 12732273]
Novak VP, Yin FC, Humphrey JD. Regional mechanical properties of passive myocardium. J Biomechan. (1994);27:403–12. [PubMed: 8188721]
Parmley WW, Chuck L. Length-dependent changes in myocardial contractile state. Am J Physiol. (1973);224:1195–1199. [PubMed: 4700639]
Patterson S, Starling EH. On the mechanical factors which determine the output of the ventricles. J Physiol. (1914);48:357–337. [PMC free article: PMC1420422] [PubMed: 16993262]
Perez NG, de Hurtado MC, Cingolani HE. Reverse mode of the Na+-Ca2+ exchange after myocardial stretch: underlying mechanism of the slow force response. Circ Res. (2001);88:376–382. [PubMed: 11230103]
Petrecca K, Atanasiu R, Grinstein S, Orlowski J, Shrier A. Subcellular localization of the Na+/H+ exchanger NHE1 in rat myocardium. Am J Physiol. (1999);276:H709–H717. [PubMed: 9950874]
Philipson KD, Nicoll DA. Sodium-calcium exchange: a molecular perspective. Ann Rev Physiol. (2000);62:111–133. [PubMed: 10845086]
Ruwhof C, van der Laarse A. Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc Res. (2000);47:23–37. [PubMed: 10869527]
Sachs F (1997) Mechanical Transduction by ion channels: How forces reach the channel. In: Cytoskeletal Regulation of Membrane Function. Ed. Stanley C Froehner, Vann Bennett. The Rockefeller University Press, New York.
Sarnoff SJ, Mitchell JH, Gilmore JP, Remensynder JP. Homeometric autoregulation in the heart. Circ Res. (1960);8:1077–1091. [PubMed: 13746560]
Sasaki N, Mitsuiye T, Noma A. Effects of mechanical stretch on membrane currents of single ventricular myocytes of guinea-pig heart. Jpn J Physiol. (1992);42:957–970. [PubMed: 1297861]
Sigurdson WA, Ruknudin A, Sachs F. Calcium imaging of mechanically induced fluxes in tissue-cultured chick heart: role of stretch-activated ion channels. Am J Physiol. (1992);262:H1110–H1115. [PubMed: 1373571]
Steele DS, Smith GL. Effects of muscle length on diastolic [Ca2+]i in isolated guinea-pig ventricular trabeculae. J Physiol. (1993);467:328P.
Stevens C, Hunter PJ. Sarcomere length changes in a 3D mathematical model of the pig ventricles. Prog Biophys Mol Biol. (2003);82:229–241. [PubMed: 12732282]
Streeter DD, Spotnitz HM, Patel DP, Ross J, Sonnenblick EH. Fiber orientation in the canine left ventricle during diastole and systole. Circ Res. (1969);24:339–347. [PubMed: 5766515]
Sung S, Mills RW, Schettler J, Narayan SM, Omens JH, McCulloch AD. Ventricular filling slows epicardial conduction and increases action potential duration in an optical mapping study of the isolated rabbit heart. J Cardiovasc Electrophysiol. (2003);14:1–11. [PubMed: 12930255]
Tavi P, Han C, Weckstrom M. Mechanisms of stretch-induced changes in [Ca2+]i in rat atrial myocytes: role of increase troponin C affinity and stretch-activated ion channels. Circ Res. (1998);83:1165–1177. [PubMed: 9831710]
Tohse N. Calcium-sensitive delayed rectifier potassium current in guinea pig ventricular cells. Am J Physiol. (1990);258:H1200–H1207. [PubMed: 2331008]
Trombitas K, Granzier H. Actin removal from cardiac myocytes shows that near Z line titin attaches to actin while under tension. Am J Physiol. (1997);273:C662–C670. [PubMed: 9277364]
Vila-Petroff MG, Kim SH, Pepe S, Dessy C, Marban E, Balligand JL, Sollott SJ. Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat Cell Biol. (2001);3:867–873. [PubMed: 11584267]
von Anrep G. On the part played by the suprarenals in the normal vascular reactions of the body. J Physiol. (1912);45:307–312. [PMC free article: PMC1512890] [PubMed: 16993158]
von Lewinski D, Stumme B, Maier LS, Luers C, Bers DM, Pieske B. Stretch-dependent slow force response in isolated rabbit myocardium is Na+ dependent. Cardiovasc Res. (2003);57:1052–1061. [PubMed: 12650883]
von Lewinski D, Stumme B, Fialka F, Luers C, Pieske B. Functional relevance of the stretch-dependent slow force response in failing human myocardium. Circ Res. (2004);94:1392–1398. [PubMed: 15105296]
White E, Boyett MR, Orchard CH. The effects of mechanical loading and changes in length on single guinea-pig ventricular myocytes. J Physiol. (1995);482:93–107. [PMC free article: PMC1157756] [PubMed: 7730993]
Yang Z, Pascarel C, Steele DS, Komukai K, Brette F, Orchard CH. Na+-Ca2+ exchange activity is localized in the T-tubules of rat ventricular myocytes. Circ Res. (2002);91:315–322. [PubMed: 12193464]
Zabel M, Koller BS, Sachs F, Franz MR. Stretch-induced voltage changes in the isolated beating heart: importance of timing of stretch and implications for stretch-activated ion channels. Cardiovasc Res. (1996);32:120–130. [PubMed: 8776409]
Zeng T, Bett GC, Sachs F. Stretch-activated whole cell currents in adult rat cardiac myocytes. Am J Physiol. (2000);278:H548–H557. [PubMed: 10666087]
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