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.

Introduction

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. 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 (L_max), 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. 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...)

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. Data are related to the force values at the end of the immediate phase (1^st). * =p<0.05 vs. 1^st 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.

Acknowledgments

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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