Stretch-induced Slow Force Response in Mammalian Ventricular Myocardium

von Lewinski D, Kockskämper J, Pieske B.

Publication Details

Stretching cardiac muscle results in an immediate followed by a delayed increase in developed force. The latter takes several minutes to develop fully and is thus termed slow force response (SFR). The SFR has been observed in different preparations (isolated myocytes, trabeculae, papillary muscles and whole hearts) of a variety of species including human myocardium, however, the underlying mechanisms are not yet completely understood. A major part of the SFR is mediated by an increase in intracellular calcium due to decreased forward and increased reverse mode of the sarcolemmal Na+/Ca2+ exchanger (NCX). This shift in activity is caused by an increase in intracellular sodium due to stimulation of the sarcolemmal Na+/H+ exchanger-1 (NHE1). However, the mechanism(s) underlying the stretch-induced stimulation of NHE1 remain elusive and not the entire SFR is mediated via this pathway. There is evidence that stretch-activated channels (SAC) play a significant role at least in some species. This article discusses the recent progress in elucidating the cellular mechanisms underlying the SFR in mammalian ventricular myocardium.


Intrinsic mechanisms of the heart enable it to adjust cardiac output to changes in hemodynamic conditions. Increases in ventricular end-diastolic volume caused either by an increase in venous return or a rise in aortic resistance is followed by an immediate increase in force of contraction. This rapid adaption is mediated by the Frank-Starling mechanism and is related to an increased sensitivity of the myofilaments for Ca2+. It allows the heart to maintain sufficient cardiac output even at elevated pre- and afterload and equalizes the output of the left and right ventricle. If the intraventricular volume remains elevated a second slower mechanism increases myocardial contractility, which is called the slow force response (SFR).

The load- and time-dependent alterations in developed force during the SFR were first described for cat papillary muscles by Parmley and Chuck in 1973 [27]. In the following three decades a delayed positive inotropic effect due to stretch was observed in a wide variety of experimental preparations including rat, cat, ferret, rabbit, guinea pig and human myocardium [7, 8, 16, 28, 36, 37, 38,], isovolumetric beating hearts [34, 35] and in vivo volume-loaded canine hearts [25]. First mechanistic insights into the SFR were provided in the early 1980s by Chuck & Parmley (1980) and Allen & Kurihara (1982), who could demonstrate an involvement of sarcoplasmic reticulum (SR) Ca2+ handling and augmented intracellular Ca2+ transients, respectively. Further extensive work was performed during the last years aiming at elucidating the signal transduction mechanisms of the SFR [3, 11, 28]. In these experiments the SFR was shown to be related to a stretch-dependent autocrine/paracrine release of angiotensin II (AT-II) and endothelin-1 (ET-1) with consecutive stimulation of the Na+/H+ exchanger (NHE) resulting in enhanced transsarcolemmal Na+ entry. This is followed by a [Na+]i-dependent Ca2+ entry via the Na+/Ca2+ exchanger (NCX) working in its reverse mode [3, 11, 28]. These experiments were performed in isolated feline and rat heart muscles. However, the crucial role of ET-1 and angiotensin II as an initial step in the SFR was challenged in later experiments using different species [7, 36, 37].

Nevertheless, there is general agreement on the downstream part of the signal transduction pathway, i.e. stimulation of NHE1 and reverse mode of the NCX. However, the upstream part is still a matter of debate and in the center of recent research efforts. Autocrine/paracrine release/action of AT-II and ET-1 does not appear to be a general mechanism underlying the SFR. Other potential mechanisms have been proposed including stretch-induced alterations in action potential duration (APD) [37], cAMP or nitric oxide (NO) signaling or in the activity of SAC [8, 36, 37]. In addition, though a SFR can also be observed in atrial myocardium, the subcellular mechanisms may differ (Kockskämper et al., unpublished data).

Changes in ion homeostasis during the SFR

Alterations in [Ca2+]i

Since myofilament-generated force is triggered by calcium binding to troponin C, the first studies on the underlying mechanisms of the SFR concentrated on possible alterations in intracellular Ca2+ handling. Indeed, compromising SR Ca2+ handling (using caffeine) inhibited the SFR [10] and direct measurements of [Ca2+]i (using aequorin bioluminescence) revealed parallel increases in intracellular Ca2+ transients and developed force during the SFR [2]. A number of studies using various cardiac preparations has confirmed these findings providing good evidence that the SFR - in contrast to the immediate force response - results from an increase in [Ca2+]i [2, 3, 20, 34].

Increases in [Ca2+]i might be either due to an increase in Ca2+ entry into the cells, a decrease in Ca2+ efflux out of the cells, changes in SR Ca2+ handling or a combination of these factors. The major pathway of calcium influx into the cardiac myocyte is via the L-type Ca2+ channels to mediate excitation-contraction coupling and Ca2+-induced Ca2+ release from the SR [14]. The sarcolemmal L-type Ca2+ channels are voltage-dependent, but a mechanosensitive component cannot be ruled out. Nevertheless, experimental data gathered so far do not support the hypothesis of stretch-induced augmented calcium influx via this pathway. Neither direct measurements of L-type Ca2+ current in isolated myocytes [16] nor the indirect test of pharmacologically blocking the L-type Ca2+ channels in cat papillary muscles [10] or trabeculae from failing human hearts [36] revealed any significant change in current or SFR. Besides L-type Ca2+-channels, Ca2+ ions might pass the sarcolemma via SACs.

There is conflicting data regarding the possible involvement of SAC in the SFR and this aspect will be discussed in more detail in part 4 of this article. Finally, an increased influx of calcium might be mediated via reverse mode of the NCX. This electrogenic counter ion transporter is present in almost every cell type. In the cardiac myocyte it usually works in the "forward mode", in which 3 Na+ enter the cell and 1 Ca2+ is extruded. Forward mode NCX activity contributes to the decline in [Ca2+]i during a Ca2+ transient. However, depending on the thermodynamic conditions, the protein can work in "reverse mode", leading to a calcium influx and a sodium efflux. Forward mode is facilitated by negative membrane potentials and high [Ca2+]i, whereas reverse mode is favored by more positive membrane potentials and elevated [Na+]i. KB-R7943, an inhibitor of the NCX that preferentially blocks the reverse mode, largely reduces the SFR in all ventricular preparations tested so far providing compelling evidence that enhanced reverse mode of the NCX mediates a major part of the SFR. However, the SFR cannot be blocked completely by KB-R7943. This is illustrated in Fig. 1 for failing human and non-failing rabbit myocardium.

Figure 1. A: Original registration.

Figure 1

A: Original registration. Effect of stretch on isometric twitch force in a muscle strip from a failing human heart. At steady state conditions, the muscle was stretched from 88% (L88) to 98% (L98) of its optimal length (Lmax), resulting in an immediate (more...)

Increased NCX reverse mode is accompanied by a decrease in forward mode per time. Therefore, intracellular Ca2+ is not only augmented due to more influx via reverse mode but also due to less efflux via forward mode. This should augment SR Ca2+ load and thus increase the amplitude of the Ca2+ transient via two mechanisms: 1) enhanced Ca2+ influx during the action potential (at positive membrane potentials) via reverse mode NCX and 2) enhanced Ca2+ release from the SR because of increased Ca2+ load and increased trigger Ca2+. There is evidence to support both mechanisms. Using rapid cooling contractures to determine SR Ca2+ content, we could directly demonstrate that SR Ca2+ load is increased during the SFR in nonfailing rabbit and failing human myocardium [36, 37] (Fig. 2). Furthermore, inhibition of SR function reduced the amplitude of the SFR consistent with previous findings in cat papillary muscles [10]. In other studies, functional block of the SR reduced force and Ca2+ transients but did not affect the magnitude of the SFR [8, 19, 20]. The latter finding of an intact SFR in the absence of a functional SR does not rule out the contribution of elevated SR Ca2+ load to the SFR but rather suggests that reverse mode NCX can contribute directly to the SFR and, therefore, provides evidence that both mechanisms, i.e. enhanced Ca2+ influx and enhanced Ca2+ release from the SR, are involved in the generation of the SFR. Variations in the effect of inhibiting the SR on the magnitude of the SFR are thus likely to represent the varying relative contributions of enhanced SR function versus enhanced Ca2+ influx to the SFR in the different species and experimental conditions used.

Figure 2. Left: Effect of stretch on twitch force and rapid cooling contractures during the SFR in failing human myocardium.

Figure 2

Left: Effect of stretch on twitch force and rapid cooling contractures during the SFR in failing human myocardium. Force and RCC data were obtained from the same muscle preparations (n=7) and normalized to the respective values at the end of the immediate phase (more...)

Alterations in [Na+]i

NCX activity depends on membrane potential and the Na+ and Ca2+ gradients over the sarcolemma. Since under physiological conditions extracellular Na+ and Ca2+ concentrations are constant, it is changes in membrane potential (e.g. during an action potential) and intracellular Na+ and Ca2+ concentrations that determine whether the NCX operates in forward or reverse mode. Elevated [Na+]i is expected to result from stretch-induced stimulation/activation of NHE1 or SAC and would thermodynamically favor the reverse mode of the NCX. Despite the central role proposed for [Na+]i in contributing to the SFR, however, surprisingly little information is available on stretch-induced alterations in [Na+]i. There are only a few studies, in which [Na+]i was measured directly during the SFR [3, 16]. In combination with functional data obtained by modulating intra- and/or extracellular [Na+] through pharmacological interventions [37], the results of these studies support the notion that stretch causes an elevation of [Na+]i followed by a secondary rise in [Ca2+]i via reverse mode NCX to increase force.

(Partial) Replacement of extracellular Na+ with Li+ inhibits the NCX. Furthermore, it reduces the inwardly directed driving force for Na+ and, hence, [Na+]i. When 50% of the extracellular Na+ was replaced by Li+, the SFR in rabbit myocardium was largely suppressed [37]. By contrast, inhibition of the Na+-K+ pump with strophantidin, which increases basal [Na+]i and force, significantly augmented the SFR suggesting that regulation of [Na+]i is intimately associated with the SFR [37]. Although an earlier study in isolated rat cardiomyoctes failed to detect significant stretch-induced changes in [Na+]i [16], direct measurements of [Na+]i in muscle strips from rat and rabbit ventricles (using the same Na+-sensitive dye SBFI) revealed increases in [Na+]i by 3–6 mmol/l during the SFR [3]. Inhibition of NHE1 activity largely reduced the stretch-induced elevation of [Na+]i and the SFR [3]. Thus, stretch stimulates NHE1 activity to increase [Na+]i and force.

Even after NHE1 blockade, however, there was still some residual stretch-dependent increase in both [Na+]i and force, implying that there are additional mechanisms by which stretch can elevate [Na+]i. SAC are a likely candidate. Indeed, it could be shown that local stretch activated SAC and increased total and free cytosolic [Na+] in mouse ventricular myocytes using electron probe microanalysis and fluorescence imaging of sodium green, respectively [18, 21]. Local stretch, however, differs significantly from the more homogenous end-to-end stretch applied to myocytes and muscle strips to elicit the SFR. Furthermore, there are contradictory data as to the possible involvement of SAC in the SFR (see below). Therefore, it remains to be established whether Na+ influx through SAC contributes to the increases in [Na+]i and force during the SFR.

Based on modeling studies [5], it was also suggested that stretch could inhibit the activity of the Na+-K+ pump and/or stimulate a Na+ leak current to increase [Na+]i and elicit a slowly developing increase in force. This is an attractive hypothesis given the observation that partial inhibition of the Na+-K+ pump by submicromolar concentrations of strophantidin significantly augmented the SFR [37]. Other than that, however, experimental data confirming or refuting this hypothesis are still lacking.

In conclusion, current evidence indicates that stretch elevates [Na+]i to increase [Ca2+]i and thus force via reverse mode NCX. The only mechanism that has been identified unambiguously to contribute to the stretch-induced [Na+]i increase is increased NHE1 activity.

Alterations in [H+]i (pHi)

If stretch-stimulated NHE1 activity increases [Na+]i, it should also increase pHi, i.e. reduce [H+]i, because for each Na+ entering the myocyte via NHE, one H+ is extruded. Intracellular alkalosis increases myofilament Ca2+ sensitivity and is associated with an increase in force. Therefore, stretch-induced stimulation of NHE1 activity could increase force via two mechanisms: elevations of [Na+]i and pHi. An increase in pHi elicited by stretch was first demonstrated in cat papillary muscles bathed in HEPES-buffered solution by Cingolani's group [11]. The pHi increase was abolished by EIPA (5μmol/l), an inhibitor of the NHE, suggesting that it was mediated by stimulation of NHE1. Because force was not measured in these experiments, a relation between the stretch-induced alkalosis and the SFR was not possible. Further experiments by the same group revealed that the SFR in rat trabeculae was indeed accompanied by an increase in pHi, but only in unphysiological HEPES-buffered and not in physiological bicarbonate-buffered solutions [3, 13]. The absence of any stretch-induced pHi changes in bicarbonate-containing solutions was also observed in cat, rabbit and human myocardium [12, 36].

Why would a detectable pHi increase occur only in HEPES- and not in bicarbonate-buffered solutions? There are at least two possible explanations for this finding. First, the H+ buffering power of ventricular myocytes is reduced by a factor of 2.3 in HEPES-buffered solution [23]. The same number of H+ leaving the cell via NHE in HEPES- or bicarbonate-containing solution would thus result in a larger increase in pHi in the presence of HEPES. Second, there are bicarbonate-dependent transporters in the sarcolemma that might counteract pHi changes by NHE in bicarbonate-buffered solution. In HEPES-buffered solution these transporters are inhibited because of the lack of substrate (bicarbonate). Recent evidence indicates that the Cl--HCO3- anion exchanger (AE) could compensate for NHE-induced alterations in pHi during the SFR. Using an antibody directed against AE3, the major isoform in cardiac myocytes, Cingolani et al. [12] could show that inhibition of AE activity resulted in a detectable stretch-induced pHi increase in cat papillary muscles bathed in bicarbonate-buffered solution. Moreover, the pHi increase was accompanied by a significant augmentation of the SFR suggesting that it contributed directly to the positive inotropic effect after stretch.

Does the pHi increase in HEPES-buffered solution contribute to the SFR? Early experiments in cat papillary muscle showed that stretch elicited a pHi increase, which started after a delay of several minutes [11]. In contrast, the SFR typically begins to develop soon (i.e. within 1 min) after the stretch. Recently, we studied this issue in more detail in rabbit ventricular myocardium (unpublished data). Our results revealed a divergence of the stretch-mediated increases in force and pHi. The SFR started soon after the stretch stimulus and reached its maximum within 10 min. pHi, on the other hand, was unchanged during this time and began to increase only after the SFR had reached its maximum. The delay between the increases in [Na+]i and pHi (both mediated by NHE stimulation) under these conditions can be explained by the large difference in buffering power for the two cations. Furthermore, when stretch-induced increases in force, pHi, and [Na+]i were compared directly in HEPES- versus bicarbonate-buffered solutions, it was found that neither the magnitude of the SFR nor the elevation in [Na+]i were altered appreciably by the buffering conditions, despite significant differences in stretch-induced pHi increases [3]. Taken together, these data suggest that even in HEPES-buffered solution stretch-induced alterations in pHi have no or only minimal impact on the SFR.

In conclusion, under physiological conditions stretch activates NHE1, but this has only minor consequence on pHi. Changes in pHi with stretch appear more pronounced in HEPES buffer, but still, of minor relevance for the SFR. Thus, in ventricular myocardium stretch-induced stimulation of NHE1 increases force mainly via elevation of [Na+]i and a secondary rise in [Ca2+]i and not via pHi-mediated alterations in myofilament Ca2+ sensitivity.

Signal transduction pathways

Although most authors agree that stimulation of NHE1 and reverse mode of the NCX mediate a major part of the SFR, there is an ongoing debate on the underlying signal transduction pathway(s). How does stretch stimulate NHE1 activity? Beginning in the late 1990s, the subcellular mechanisms for the delayed inotropic response to stretch were investigated in more detail. Using feline myocardium, Cingolani and coworkers reported that stretch-dependent autocrine/paracrine activation of AT-II and ET-1 receptors caused the SFR [3]. They demonstrated in this model that autocrine/paracrine release of AT-II followed by autocrine/paracrine release of ET-1 mediates the stimulation of the NHE1. The stretch-dependent release of AT-II and ET-1 from isolated myocardium was in line with previous work of Sadoshima and Izumo [30], who first demonstrated in cultured rat cardiac myocytes that stretch-induced autocrine release of AT-II mediates hypertrophy. In ferret papillary muscles [7] it was found that ET-1, but not AT-II, is involved in the generation of the SFR. In nonfailing rabbit and failing human myocardium, however, we could not confirm the contribution of either AT-II or ET-1 to the stretch-dependent SFR [36, 37]. Therefore, it appears that there are species-dependent differences in the signal transduction pathways mediating the stretch-induced stimulation of NHE1 and that autocrine/paracrine release and action of AT-II and ET-1 is not a universal mechanism.

Several lines of evidence suggest a role for cAMP signaling in the stretch -induced SFR. Direct measurements of [cAMP] in ferret papillary muscles and dog hearts revealed a ~50% increase in [cAMP] following stretch [6, 34]. This response was absent in muscle strips that did not show a SFR [6]. Furthermore, the stretch-induced SFR was abolished or even reversed by pre-application of the β-adrenergic agonist isoprenaline in rabbit papillary muscles [19] (and own unpublished data) or in canine hearts [34] and significantly reduced by the cAMP antagonist Rp-8-Br-cAMPS in ferret papillary muscles [6]. Inhibition of β-adrenergic receptors by esmolol did not affect the SFR in canine hearts [34], but in our hands propranolol increased the SFR in rabbit papillary muscles (unpublished data). Since reserpine was without effect on the stretch-dependent SFR [27,34] a possible involvement of catecholamine release from intracardiac nerve terminals can be excluded as an underlying mechanism. Nevertheless, stretch-induced elevation of [cAMP] might be involved in the SFR. The source of this [cAMP] increase, however, remains elusive.

A further potential candidate for mediating stretch-induced inotropy is the nitric oxide (NO) system. The NO system has been implicated in the modulation of basal contractility and SR Ca2+ handling [31]. More specifically, ryanodine receptors have been shown to be directly regulated by NO-dependent nitrolysation [39]. In isolated rat cardiomyocytes, inhibition of NO synthesis with L-NAME prevented the stretch-induced increase of Ca2+ spark frequency and Ca2+ transients, suggesting an important role for NO in stretch-induced contractile activation [29]. The stretch-induced increase in Ca2+ cycling was absent in cardiomyocytes isolated from endothelial NO synthase knockout mice [29]. In vitro experiments using L-NAME (1 mmol/l) as a pharmacological blocker of NO synthase, however, did not reduce the SFR in both papillary muscles and single myocytes of adult rats8 and failing human myocardium [36]. In line with these findings, exogenous NO may even decrease contractility in isolated trabeculae from failing and non-failing human hearts [15]. Thus, like AT-II and ET-1 release, stretch-dependent NO signaling may not be a universal mechanism mediating the SFR and may be operative only in certain species or under certain experimental conditions.

Involvement of stretch-activated channels and changes in action potential configuration in the SFR

Non-selective cationic stretch-activated channels (SAC) might conduct Na+ as well as Ca2+ ions into the myocyte and thus mediate stretch-dependent inotropy. Using a theoretical model of atrial myocytes it has been postulated that the stretch-induced slow increase in intracellular calcium (and force) can be mimicked by introducing a SAC into the algorithm. Furthermore, this model has shown comparable effects on Ca2+ handling by either SAC activation or NHE stimulation [32, 33]. Experimental data on the possible involvement of SAC in the development of the stretch-dependent SFR are contradictory, however, and the findings may depend on the species, experimental model and SAC-blocking agent used.

We tested in our laboratory whether SACs are involved in the SFR of non-failing rabbit or failing human myocardium. Muscle strips were preincubated with the SAC inhibitor gadolinium (10 μmol/L) in both species. These experiments did not support a role of SACs for the SFR [36, 37].

However, not all subtypes of SACs are blocked with gadolinium [17] and it is not completely specific for SACs [40]. To further elucidate the relevance of SACs in potentially mediating part of the SFR we used streptomycin (70 μmol/L), another SAC blocker, in a second set of experiments in failing human myocardium. Both interventions did not affect the SFR (Figure 3, left for gadolinium and right for streptomycin). Twitch force increased to 120±3% before and to 121±3% in the presence of gadolinium in human myocardium (120±3% and 121±3% for rabbit myocardium; data not shown) and to 122±6% before and to 126±6% in the presence of streptomycin. In addition, SAC blockade did not affect basal contractility or the immediate response to stretch. By contrast, Calaghan and White (2004) demonstrated a significant decrease of the SFR as well as of the parallel increase in Ca2+ transients in rat papillary muscles using 80 μmol/L streptomycin [8]. In isolated myocytes from the same animals the SFR was largely inhibited by 40 μmol/L streptomycin [8]. Thus, there is evidence both to support and reject a role for SACs in the SFR in ventricular myocardium.

Figure 3. Influence of gadolinium (10 μmol/L; n=11, left) or streptomycin (70μmol/L; n=6, right) on the slow force response.

Figure 3

Influence of gadolinium (10 μmol/L; n=11, left) or streptomycin (70μmol/L; n=6, right) on the slow force response. Data are related to the force values at the end of the immediate phase (1st). * =p<0.05 vs. 1st phase.

Stretch-induced alterations in intracellular ion concentrations (e.g. Na+ and Ca2+) as well as modulation of ion currents (e.g. currents carried by SACs or NCX) could potentially change the configuration of the action potential (AP). Both, AP prolongation [1] and AP shortening [22, 24] have been described following stretch in mammalian myocardium. Since Ca2+ entry through voltage-dependent Ca2+ channels occurs during depolarisation, a stretch dependent prolongation of AP duration might underlie the SFR and the observed increase in SR Ca2+ content. In addition, prolonged depolarisation might also favor reverse-mode NCX Ca2+-entry [4]. However, we did not observe any effect of stretch on AP duration or resting membrane potential in isolated rabbit trabeculae [37], consistent with previous work in sheep Purkinje fibers [9] and Langendorff perfused canine hearts [26].

Conclusions and perspectives

The SFR is a general phenomenon intrinsic to the mammalian myocardium. It appears to be an additional physiological mechanism to adapt stroke volume to increases in hemodynamic load and could therefore be of functional relevance in the volume overloaded heart. It enlarges the immediate effects of the Frank-Starling mechanism. In contrast to the immediate force response, the SFR is not associated with increased myofilament Ca2+ sensitivity but rather appears to be mediated by stretch-dependent stimulation of the NHE1 and, possibly, activation of SACs. The NHE1-mediated elevation of [Na+]i favors the reverse mode of the NCX and, thereby, augments SR Ca2+ load and Ca2+ transients, which ultimately underlies the slow increase in force.

The signal transduction pathway(s) leading to the stimulation of the NHE1 have not been identified unambiguously yet and seem to depend on the experimental setting, particularly on the species used. In addition, not the entire SFR is mediated via this best characterized NHE1-dependent mechanism. Activation of SACs might play a role as well as other mechanisms that have yet to be identified. Stretch-induced autocrine/ paracrine release/action of AT-II and ET-1, increases in [cAMP] and NO signaling have all been proposed to underlie the SFR, but none of these pathways has gained general acceptance. It is likely that direct stimulation of NHE1 (or of other membrane transporters such as the NCX) by mechanical signals or indirect stimulation through distinct mechanosensors, such as focal adhesions or cytoskeletal proteins, might contribute to the SFR. Clearly, future research will focus on these issues and help unravel the signaling pathways and cellular mechanisms underlying the SFR and better define its physiological and clinical relevance.


The authors would like to thank the Deutsche Forschungsgemeinschaft (DFG) for continuous support of their work (research grants to BP, PI-414/1-4).


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