More Info
                                                              Max Lab
   Imperial College School of Science Technology & Medicine, National Heart & Lung Institute,
                  Charing Cross Campus, Margravine Road, London, W6 8RF, UK.
Since their definitive description, using patch electrophysiology in skeletal muscle, [1] stretch activated
channels (SACS – depicted in the membrane channel, fig) have been described in heart [2]. Characteristics
of the channel electrophysiology have found equivalence in intact heart, where monophasic action potentials
(MAPs) can be used to gain qualitative insights into cellular electrophysiology: for example isolated
perfused heart of: frog [3], and mammals [4-6]. Notably, there is a “reversal” potential, [3, 7] where a stretch
early in the action potential produces a repolarising tendency, whereas late it produces depolarisation. There
is no change at the “reversal potential”. The equivalence extends to intact heart in situ, in experimental
preparations, [8], and to man [9].
MEF could be a homeostatic feedback mechanism (see [10]) and has also been mathematically modelled
[11]. Of particular relevance is that an exacting mechanical perturbation in the feedback loop can give rise to
clinically relevant premature beats not only in left ventricle, but in right ventricle, [12] as well as in atria
(reviewed in [13]).
Ventricular premature beats can lead to life threatening arrhythmia. MEF is increasingly being highlighted as
a possible cause of sudden arrhythmic cardiac death in man, (see reviews: [14-16]). If this is the case MEF
should also feature in clinical correlations or predictors of mortality. This is apparent in correlations with
ventricular ejection fraction - a purely mechanical rather than electrophysiological predictor [17-19]. How
does MEF relate to other factors related to mortality? For example β blockade is one of the few
pharmacological interventions that curtail mortality. We investigated this aspect, suspecting that alternative
mechanoelectric transducers may reside in cell “signalsomes” associated with the β receptor (see fig, cell
signal, SACs/channels/receptors). We have shown that this signalsome is involved in mechanically induced
electrophysiological changes. This includes: the electrical restitution curve [20]; exacerbating by β agonism
(unpublished), or blocking by β blockade [21] mechanically induced arrhythmia. This notion has been
further supported: [22]. Raised intraventricular pressure releases catecholamines from the ventricle [23] and
this could affect the cell signal chain involving β agonist/receptor, ATP, cAMP, and Ca channels. In support
of catecholamine release our laboratory has found that catecholamine store depletion, either
pharmacologically [24], or by chronic sympathetic denervation [25] curtails mechanoarrhythmia.
Is there evidence of further crosstalk? Any membrane channel associated
with the cytoskeleton could provide a candidate (see fig,                            Cell stress/strain is distributed to several potential
                                                                                      mechanotransducers to affect electrophysiology.
SACs/channels/receptors), for stress-strain could be transmitted to the
channel in this way. The ATP activated potassium (KATP) channel is                                                        Cytoskeleton

attached to the cytoskeleton, and has been suggested to be                                                                  *                Integrin

mechanosensitive [26], as is possibly the L type Ca channel [27].                                            *
                                                                                                        strain             Cell signal

Recently, our laboratory [28] has shown that several ion channels are                                                           *                            -
regionally fixed in the membrane over time, implicating the cytoskeleton.                       *                                                Extracell

This means that they could potentially be subject to transmitted forces.                              Mechanotransducer
                                                                                                                                  *               matrix

Although this makes them candidates for mechanoelectric transduction,                             *    Sites/complexes                             Ion/ligand

we have yet to investigate this aspect. However, several other channels
may be mechanosensitive, including sodium channels [29] and potassium channels such as TREK-1 ([30],
which appears not to involve the cytoskeleton), and IKAA [31], ion exchangers [32].
Other cell signalsomes have also been implicated as being mechanosensitive and, mostly via intracellular Ca,
affect membrane electrophysiology. Crosstalk could be provided by AT2 and ET1 receptors, (see brief
overview [10]) which would affect PLC via Gq. This can alter intracellular Ca, first, via IP3 and SR Ca
release, and second through PLC to facilitate membrane translocation (DAG/RACK/PKC) to influence Na/H
exchange, and so intracellular Na to affect electrogenic Na/Ca exchange. An under-investigated but
potentially important mechanism invokes mechanically-induced changes in ATP [33].
In conclusion, mechanoelectric crosstalk embraces a plethora of channels, exchangers, and cell
“signalsomes”. If deranged mechanoelectric feedback contributes mortality, there is a deluge of potential
therapeutic targets.
1.    Guharay, F. & Sachs, F. (1984). Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal
      muscle. J.Physiol. 352, 685-701.
2.    Craelius, W., Chen, V., & el Sherif, N. (1988). Stretch activated ion channels in ventricular myocytes. Biosci.Rep. 8, 407-414.
3.    Lab M J (1978). Mechanically dependent changes in action potentials recorded from the intact frog ventricle. Circ.Res. 42,
4.    Hansen, D. E., Craig, C. S., & Hondeghem, L. M. (1990). Stretch-induced arrhythmias in the isolated canine ventricle:
      evidence for the importance of mechano-electrical feedback. Circ. 81, 1094-1105.
5.    Dick, D. J., Harrison, F. G., O'Kane, P. D., & Halliwell, O. T. (1993). "Preconditioning" of mechanically induced premature
      ventricular beats in the isolated rabbit heart. J Physiol 459, 509P.
6.    Franz, M. R., Burkhoff, D., & Yue, D. T. Mechano-electrical feedback in the intact isolated perfused canine heart. Circ Supp
      III, 382. 1985: Abstract
7.    Zabel, M., Koller, B. S., Sachs, F., & Franz, M. R. (1996). Stretch-induced voltage changes in the isolated beating heart:
      importance of the timing of stretch and implications for stretch-activated ion channels. Cardiovasc Res 32, 120-130.
8.    Dean, J. W. & Lab, M. J. Effects of changes in afterload on the absolute refactory period of the pig ventricle. PACE. 10, 987.
      1987: Abstract
9.    Taggart, P., Sutton, P. M., Treasure, T., Lab, M. J., et al. (1988). Monophasic action potentials at discontinuation of
      cardiopulmonary bypass: evidence for contraction-excitation feedback in man. Circ. 77, 1266-1275.
10.   Lab, M. J. (1999). Mechanosensitivity as an integrative system in the heart: an audit. Prog.Biophys Mol.Biol 71, 7-27.
11.   Kohl, P., Hunter, P., & Noble, D. (1999). Stretch-induced changes in heart rate and rhythm: clinical observations, experiments
      and mathematical models. Prog Biophys Mol Biol 71, 91-138.
12.   Greve, G., Lab, M. J., Chen, R., Barron, D., et al. (2001). Right ventricular distension alters monophasic action potential
      duration during pulmonary arterial occlusion in anaesthetised lambs: evidence for arrhythmogenic right ventricular
      mechanoelectrical feedback. Exp Physiol 86, 651-657.
13.   Nazir, S. A. & Lab, M. J. (1996). Mechanoelectric feedback and atrial arrhythmias. Cardiovasc Res 32, 52-61.
14.   Dean, J. W. & Lab, M. J. (1989). Arrhythmia in heart failure: role of mechanically induced changes in electrophysiology.
      Lancet 1, 1309-1312
15.   Franz, M. R. (1996). Mechano-electrical feedback in ventricular myocardium. Cardiovasc Res 32, 15-24.
16.   Reiter, M. J. (1996). Effects of mechano-electric feedback: potential arrhythmogenic influence in patients with congestive heart
      failure. Cardiovasc Res 32, 44-51.
17.   Kelly, M., Thompson, P., & Quinlan, M. (1985). Prognostic significace of left ventricular ejection fraction after acute
      myocardia infarction. Br Heart J 53, 16-24.
18.   Copie, X., Hnatkova, K., Blankoff, I., Staunton, A., et al. (1996). Risk of mortality after myocardial infarction: value of heart
      rate, its variability and left ventricular ejection fraction. Arch Mal Coeur Vaiss 89, 865-871.
19.   Odemuyiwa, O., Malik, M., Farrell, T., Bashir, Y., et al. (1991). Multifactorial prediction of arrhythmic events after myocardial
      infarction. Combination of heart rate variability and left ventricular ejection fraction with other variables. PACE 14, 1986-
20.   Horner, S. M., Murphy, C. F., Coen, B., Dick, D. J., & Lab, M. J. (1996). Sympathomimetic modulation of load-dependent
      changes in the action potential duration in the in situ porcine heart. Cardiovasc Res 32, 148-157
21.   Lab, M. J., Dick, D., & Harrison, F. G. Propranolol reduces stretch arrhythmia in isolated rabbit heart. J Physiol 446, 539P.
      1992: Abstract.
22.   Lerman, B.B, Engelstein, ED & Burkhoff, D. (2001). Mechanoelectrical feedback: role of beta-adrenergic receptor activation
      in mediating load-dependent shortening of ventricular action potential and refractoriness. Circ 104, 486-490.
23.   La Farge, C. G., Monroe, R. G., Gamble, W. J., Rosenthal, A., & Hammond, R. P. (1970). Left ventricular pressure and
      norepinephrine efflux from the dennervated heart. Am J Physiol 219, 519-524.
24.   Dick, D. J., Lab, M. J., Harrison, F. G., Green, S., & Gruber, P. C. (1994). A possible role of endogeneous catecholamines in
      stretch induced premature ventricular beats in the isolated rabbit heart. J Physiol 479, 133P.
25.   Drake-Holland, A. J., Noble, M. I., & Lab, M. J. (2001). Acute pressure overload cardiac arrhythmias are dependent on the
      presence of myocardial tissue catecholamines. Heart 85, 576.
26.   Van Wagoner, D. R. (1993). Mechanosensitive gating of atrial ATP-sensitive potassium channels. Circ Res 72, 973-983.
27.   Matsuda, N., Hagiwara, N., Shoda, M., Kasanuki, H., & Hosoda, S. (1996). Enhancement of the L-type Ca2+ current by
      mechanical stimulation in single rabbit cardiac myocytes. Circ Res 78, 650-659.
28.   Gu, Y., Gorelik, J., Spohr, H. A., Shevchuk, A., et al. (2002). High-resolution scanning patch-clamp: new insights into cell
      function. FASEB J 16, 748-750.
29.   Tabarean, I. V., Juranka, P., & Morris, C. E. (1999). Membrane stretch affects gating modes of a skeletal muscle sodium
      channel. Biophys J 77, 758-774.
30.   Maingret, F., Honore, E., Lazdunski, M., & Patel, A. J. (2002). Molecular basis of the voltage-dependent gating of TREK-1, a
      mechano- sensitive K(+) channel. Biochem Biophys Res Comm 292, 339-346.
31.   Kim, D. (1992). A mechanosensitive K+ channel in heart cells. Activation by arachidonic acid. J Gen Physiol 100, 1021-1040.
32.   Perez, N. G., de Hurtado, M. C., & Cingolani, H. E. (2001). Reverse mode of the Na+-Ca2+ exchange after myocardial stretch:
      underlying mechanism of the slow force response. Circ Res 88, 376-382.
33.   Kawakubo, T., Naruse, K., Matsubara, T., Hotta, N., & Sokabe, M. (1999). Characterization of a newly found stretch-activated
      KCa,ATP channel in cultured chick ventricular myocytes. Am J Physiol 276, H1827-H1838.

To top