© 1999 American Heart Association, Inc.
Editorial |
A Role for the Sarcolemmal Na+/H+ Exchanger in the Slow Force Response to Myocardial Stretch
From the Centre for Cardiovascular Biology & Medicine, King's College London, London, UK.
Correspondence to Dr J.C. Kentish, Centre for Cardiovascular Biology & Medicine, King's College London, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, UK. E-mail jon.kentish{at}kcl.ac.uk
Key Words: Na+/H+ exchanger • stretch • Anrep effect • angiotensin II • endothelin
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Introduction |
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 Top Introduction The Contractile Response to...The Hypertrophic Response to...The Role of the...References |
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Although the contractile performance of the myocardium is under continuous nervous and hormonal regulation, the myocardium possesses a number of intrinsic, load-dependent mechanisms by which it can adjust cardiac output to meet the needs of the circulation over periods ranging from seconds to years. In isolated hearts, an increase in ventricular end-diastolic volume (EDV), produced by increased venous return or decreased aortic outflow, leads immediately to a more powerful contraction via the Frank-Starling mechanism ("heterometric autoregulation"1 ), so that cardiac output increases over a few beats to match venous return. However, over the next few minutes, there is a further increase in myocardial performance, such that EDV returns toward its original value. This second autoregulatory mechanism, the "Anrep effect"2 or "homeometric autoregulation,"1 allows a given change in cardiac output to be achieved with a smaller change in EDV than if the Frank-Starling effect were the only compensatory mechanism. Finally, if the increase in EDV or wall stress is maintained, genes are switched on that eventually lead to myocardial cell hypertrophy.
Much is known about the cellular and molecular basis of the Frank-Starling mechanism and of the initial stages of load-induced hypertrophy, but the processes responsible for the Anrep effect are poorly understood. In this issue of Circulation Research, Alvarez et al3 suggest a novel mechanism for the slow increase in myocardial contractility: a stretch-induced activation of the sarcolemmal Na+/H+ exchanger (NHE) by local autocrine/paracrine systems involving angiotensin II (Ang II) and endothelin-1 (ET-1).
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The Contractile Response to Stretch of the Myocardium |
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TopIntroductionThe Contractile Response to...The Hypertrophic Response to...The Role of the...References |
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Our knowledge of the cellular mechanisms involved in the time-dependent increase in contractility after myocardial fiber stretch has come chiefly from studies in which fiber length is controlled (for reviews, see References 44 –6). Parmley and Chuck7 were the first to show that stretch of isolated papillary muscle leads to a rapid increase in active force (corresponding to the Frank-Starling mechanism in the intact heart), followed by a further increase in force over several minutes (analogous to the Anrep effect). The slow increase in force (here termed the "slow force response") has subsequently been confirmed in a range of isometrically contracting preparations, from isolated myocardial cells8 to isovolumic hearts in vitro,9 10 and in volume-loaded hearts in vivo.11 The immediate increase in force appears to be due to length-dependent properties of the cardiac myofibrils, chiefly an increase in their sensitivity to [Ca2+]i.4 In contrast, the slow force response can be explained qualitatively8 10 12 and quantitatively13 by a slow increase in the magnitude of the intracellular Ca2+ transient. However, the mechanism responsible for this slow potentiation of the Ca2+ transient has remained obscure. It cannot be explained by a length dependence of sarcoplasmic reticulum (SR) Ca2+ handling itself, because the slow force response remains in the presence of specific SR inhibitors.13 14 15 Other mechanisms could involve the observed stretch-induced increases in second messengers such as cAMP10 or InsP3,16 although how these could increase the Ca2+ transient, in a way that does not depend on the SR, remains to be examined. Activation of myocardial stretch-activated channels (see Reference 1717 for review) could enhance the Ca2+ transient by increasing (directly or indirectly) diastolic [Ca2+]i, which would allow the SR to take up and release more Ca2+. However, recent studies8 14 have failed to find any increase in diastolic [Ca2+]i that could account for the potentiation of the Ca2+ transient. Ca2+ entry could also be increased if the Ca2+ current (ICa) of the action potential were stretch sensitive, but this appears not to be the case.8 One transport process that has received little attention has been the sarcolemmal NHE, which regulates pHi by extruding H+ from the cell in a 1:1 exchange with Na+ ions. Stimulation of the NHE could potentially increase force, by either (1) increasing cell pHi, which would increase myofibrillar Ca2+ sensitivity, SR Ca2+ loading, and ICa (for review, see Reference 1818 ), or (2) increasing cell [Na+]i, which would tend to reduce Ca2+ extrusion from the cell during diastole via forward-mode Na+/Ca2+ exchange, and raise Ca2+ entry during the action potential via reverse-mode Na+/Ca2+ exchange. Stimulation of the NHE has been implicated in the positive inotropic actions of Ang II and ET-1 (reviewed in Reference 1919 ), but evidence that the NHE and these hormones may play a part in the responses of the myocardium to stretch has come from another area of cardiac research: the triggering of cellular hypertrophy by stretch.
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The Hypertrophic Response to Stretch of the Myocardium |
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TopIntroductionThe Contractile Response to...The Hypertrophic Response to...The Role of the...References |
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The past decade has seen major advances in our understanding of the events that couple myocardial stretch to cellular hypertrophy. Changes triggered by stretch of myocardial cells include the activation of "intermediate-early" genes, such as c-fos, followed by "late-responsive" genes such as fetal contractile protein genes (eg, those for ß-myosin and skeletal
-actinin). Multiple signal transduction pathways are
activated, including phospholipases C, D, and
A2, and many types of protein kinase, including
protein kinase C, tyrosine kinase, and the Raf-1 and
mitogen-activated protein kinase (MAPK)
cascades.20 21 22 The initial response to stretch is
rapid: intermediate-early genes and the signaling pathways are switched
on within minutes, ie, on the same time scale as the slow force
response. These changes may be due, at least in part, to the stretch-induced activation of local (ie, intracardiac) autocrine systems. It is known that myocardial cells possess local renin-angiotensin23 and endothelin systems.24 Using neonatal rat ventricular myocytes cultured on an elastic silicone substrate, it has been shown that stretch stimulates secretion of Ang II20 21 22 25 and ET-122 25 and that released Ang II alone,20 or both hormones,22 25 induces activation of MAPK, c-fos, etc. The importance of these autocrine systems in the intact adult heart is less clear, because adult cells have a different expression of genes and a different complement of receptors compared with neonatal cells. In addition, the myocardium possesses endothelial cells and fibroblasts, both of which may release Ang II or ET-1 in response to stretch and so could influence myocardial gene expression via a paracrine mechanism. In vivo, the situation is even more complex, and the hypertrophic effects of other factors such as sympathetic stimulation may become dominant.26
The local stretch-induced release of Ang II or ET-1 by the autocrine/paracrine pathways might be expected to stimulate the NHE, given that exogenous Ang II or ET-1 will do this. Indeed, Yamazaki et al22 recently demonstrated a stretch-induced activation of the NHE that triggered a hypertrophic response via an increase of pHi, although unexpectedly this effect appeared to be independent of autocrinely released Ang II or ET-1. Cingolani's group has now linked the contractile and molecular effects of myocardial cell stretch, by demonstrating a stretch-induced activation of the NHE that may account for the slow force response.
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The Role of the NHE in the Slow Force Response to Muscle Stretch |
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TopIntroductionThe Contractile Response to...The Hypertrophic Response to...The Role of the...References |
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If stretch activates the NHE, this should tend to increase pHi and [Na+]i. Cingolani et al27 found previously that stretch of cat papillary muscle did indeed produce a rise of pHi over
10
minutes. This alkalosis was due to the activation of the NHE, as it was
abolished by the NHE blocker EIPA. The essential role of Ang II was
shown by the demonstration that the alkalosis was also blocked by the
AT1 antagonist
losartan. Interestingly, this seemed not to be a direct effect
of Ang II on the NHE, given that the rise in pHi
produced by stretch (or by exogenous Ang II) was also inhibited by ET-1
antagonists. Cingolani et al27 suggested that
Ang II, released from the papillary muscle (or added exogenously),
caused the local release of ET-1, which then activated the NHE,
and thereby increased pHi. This agreed with
previous studies showing that Ang II could induce the synthesis and/or
release of ET-1 from myocardial cells, fibroblasts, or
endothelial cells (see References 27 and 2827 28 ). The
conclusions27 were that stretch of an intact cardiac
muscle caused the sequential release of endogenous Ang II
and ET-1, both of which thus acted in an autocrine/paracrine role, and
that the resulting increase in pHi was mediated
by stimulation of the NHE by ET-1.
In the present study,3 Cingolani's group has extended
their work by investigating the contractile consequences of this
stretch-induced stimulation of the NHE. Using isolated rat
trabeculae, they confirmed that muscle stretch increased
pHi (measured from all the cells in the
preparation) when the muscle was bathed in HEPES-Tyrode's solution but
found that pHi did not change significantly in
Tyrode's solution containing
CO2/HCO3-
buffer (perhaps because an acid-loading
Cl-/HCO3-
exchanger was activated by Ang II). Because the slow force
response was the same under both conditions, it was unlikely to be due
to the increase in pHi. There was however a
marked increase in [Na+]i
after the stretch, with a time course similar to, or perhaps slightly
preceding, the rise of force. The role of the NHE in the rise of both
[Na+]i and force was
confirmed by the finding that EIPA inhibited the rise in both
measurements. The stretch-induced changes in
[Na+]i and force were
also reduced by AT1 or ET-1
antagonists, confirming the primary roles of both hormones
in the ionic and contractile changes. The slow increase in the
magnitude of the Ca2+ transient was also blocked
by these antagonists. Provided that all the
antagonists used were acting specifically, the data from
both studies3 27 lead to the following suggested mechanism
for the slow force response:
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One uncertainty in the above scheme is how exactly the rise in [Na+]i promotes a rise in the Ca2+ transient. Alvarez et al3 detected no increase in diastolic [Ca2+]i after stretch of the muscles, as found previously,8 14 which suggests that the rise in [Na+]i does not load the cell with Ca2+ by decreasing diastolic Ca2+ extrusion via Na+/Ca2+ exchange; there could be, however, an enhancement of Ca2+ influx during the action potential via reverse-mode Na+/Ca2+ exchange. Interestingly, a recent ionic model of the myocyte29 showed that the latter effect could account for many characteristics of the slow force response (although in the model the rise in [Na+]i was considered to be most likely due to Na+-K+ pump inhibition). On the other hand, it is not clear whether the rise in [Na+]i is a vital step in the slow force response. Some studies have reported that the inotropic effect of Ang II is not due to a rise in the Ca2+ transient but to the rise in pHi,30 and in isolated myocytes there was no increase in [Na+]i during the slow increase in contractile state after stretch.8 From the latter result, it could be suggested that there are at least two mechanisms for the slow force response: an [Na+]i-independent one seen in isolated myocardial cells and another, conferred by endothelial (endocardial) cells or fibroblasts in cardiac muscle preparations, that acts to increase [Na+]i. Another source of variability may be that NHE stimulation can potentially increase force by either of two ionic mechanisms (increase in [Na+]i, and thus [Ca2+]i, or increase in pHi), so one or the other of these might predominate during the inotropic response to stretch or Ang II, depending on the experimental conditions. The precise roles of changes in [Na+]i, pHi, and of other potential mechanisms in the slow force response to stretch will need to be established by further quantitative studies. In this regard, it may be noted that the muscles used in the study by Alvarez et al3 27 were superfused rather than perfused, which might enhance the autocrine/paracrine effects compared with slightly better perfused preparations, such as isolated myocytes and perfused hearts.
A number of other questions remain, including: Are myocardial cells, endothelial cells, or fibroblasts the primary source of secreted Ang II or ET-1? How does stretch cause the release of Ang II, and what is the mechanosensor (stretch-activated channels, cytoskeleton, etc.)? How exactly is the NHE stimulated by Ang II and/or ET-1, and which kinases are involved upstream and possibly downstream of NHE? Are these mechanisms important in the intact heart? Thus, more work is needed before we can fully understand the precise mechanism(s) by which stretch increases the contractile state of isometrically contracting preparations and working hearts. Nevertheless, the study by Alvarez et al3 has suggested a novel and important role for a stretch-induced release of Ang II by an autocrine/paracrine mechanism, and for the subsequent stimulation of the NHE, in the contractile response of the myocardium to stretch.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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