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Journal of Physiology (2002), 539.1, p. 1
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.015586
Email: k.t.macleod{at}ic.ac.uk
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Cells are able to maintain generally quite substantial ionic gradients across their plasma membranes despite having to overcome fluxes of ions leaking into them. In time, the leak fluxes would dissipate the gradients upon which many membrane transport mechanisms depend. Energy-requiring processes are needed to maintain the ionic gradients in the face of the dissipative fluxes.
In common with many cell types, mammalian heart cells control their intracellular Na+ and K+ concentrations with the Na+,K+-ATPase (or Na+-K+ pump) which, in every cycle under normal physiological conditions, uses the energy derived from the hydrolysis of 1 molecule of ATP to expel 3 Na+ ions from the cell and pump 2 K+ ions into the cell.
A distinguishing feature of cardiac muscle cells is that the intracellular Na+ concentration ([Na+]i) plays a key role in the regulation of contraction. This is because the transmembrane Na+ gradient affects the function of the sarcolemmal Na+-Ca2+ exchange. The direction of ion movement on the Na+-Ca2+ exchange is dependent on membrane potential, and the extracellular and intracellular concentrations of Na+ and Ca2+. The potential at which ion movement switches direction is called the reversal potential. A key concept in cardiac cell Ca2+ regulation is that, because the reversal potential is readily encountered under physiological conditions and can be changed by small changes in [Na+]i, the efflux of Ca2+ from the cell is very dependent on [Na+]i. Factors that influence the [Na+]i will ultimately affect the intracellular Ca2+ concentration and thus both twitch and passive (tonic) force production.
A puzzling feature of cardiac cell Ca2+ regulation is that mammalian species do not behave in the same way. While most species appear to release Ca2+ from the sarcoplasmic reticulum (SR) by Ca2+ influx across the sarcolemma, the extent to which contraction relies on Ca2+ from the SR or from Ca2+ influx, varies. Contraction of rat ventricle is very dependent on the SR; guinea-pig and rabbit ventricular contractions much less so (Bers, 1985). Further, rat ventricle usually displays a negative force-frequency response and a potentiation of the twitch after a rest. In contrast, rabbit ventricle shows a positive force-frequency relationship and rest decay (a gradual decrease in the size of the first twitch following rest).
Shattock & Bers (1989) found that [Na+]i was greater in rat ventricular tissue compared with rabbit. They concluded that, because of the greater [Na+]i, Ca2+ entry via Na+-Ca2+ exchange could be favoured during rest. This Ca2+ would be pumped into the SR where it would be available for release and the more loaded SR (compared with guinea-pig or rabbit; see Terracciano & MacLeod, 1997) may explain the observation of rest potentiation. On the other hand, a lower [Na+]i measured in the rabbit would favour Ca2+ efflux during rest and so explain rest decay.
It was not known why rat cells had greater [Na+]i. In this issue of The Journal of Physiology, the paper by Despa et al. (2001) allows our understanding of cardiac cell ion homeostasis to progress a stage further. Despa et al. have repeated the measurements of [Na+]i in rat and rabbit cardiac myocytes using a different technique from that used by Shattock & Bers and studied the rate of Na+ efflux from the cells as a function of the change in [Na+]i. They confirmed that [Na+]i was greater in rat cells compared with rabbit and found that the former had a higher Vmax for Na+ efflux and a higher Km. At resting [Na+]i, Na+ efflux was greater in the rat, yet [Na+]i was higher. The finding could be explained by another observation that the dissipative Na+ flux was 2-4 times greater in the rat than rabbit. They concluded that the greater [Na+]i in rat is primarily due to a larger Na+ influx.
The article raises many points for discussion and speculation but three immediately spring to mind. To combat a larger dissipative flux a larger number of pumps are required, which, although energetically expensive for the cell, may provide tighter control over changes in [Na+]i (Eisner, 1990). One could speculate that this is a mechanism whereby hearts from animals with high and wide ranges of heart rate limit changes in [Na+]i and so their contractile response.
Secondly, the degree to which the SR of a cardiac cell is loaded with Ca2+ is dependent upon a plethora of factors. However, an important modulating mechanism is one dependent on [Na+]i, which, in turn, is dependent on dissipative Na+ influx.
Thirdly, given that [Na+]i changes in a wide variety of pathophysiological conditions, the work provides useful new insights into how Na+, and therefore Ca2+, may be controlled (or not) in such circumstances. The paper provides fresh quantitative evidence that supports some established ideas and will help in our understanding of the changes in cardiac contractility.
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REFERENCES |
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| BERS, D. M. (1985). American Journal of Physiology 248, H366-381 | |
| DESPA, S., ISLAM, M. A., POGWIZD, S. M. & BERS, D. M. (2001). Journal of Physiology 539, 133-143 | |
| EISNER, D. A. (1990). Experimental Physiology 75, 437-457 | |
| SHATTOCK, M. J. & BERS, D. M. (1989). American Journal of Physiology 256, C813-822 | |
| TERRACCIANO, C. M. N. & MACLEOD, K. T. (1997). Biophysical Journal 72, 1319-1326 |
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