The role of the Na(+)‐Ca2+ exchanger in the rate‐dependent increase in contraction in guinea‐pig ventricular myocytes.

Harrison, SM; Boyett, Mark R.

doi:10.1113/jphysiol.1995.sp020539

Cited by 31 publications

(16 citation statements)

References 24 publications

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“…Faster pacing also increases diastolic calcium. The rise in calcium at high rates depends primarily on the corresponding accumulation of sodium, due to the activity of I NCX 26 . Another mechanism that promotes calcium loading at high rates is that the action potential waveform spends more time per period at plateau potentials, and so the time spent in the calcium efflux mode is reduced.…”

Section: Discussionmentioning

confidence: 99%

New experimental evidence for mechanism of arrhythmogenic membrane potential alternans based on balance of electrogenic INCX/ICa currents

et al. 2012

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Background Computer simulations have predicted that the balance of various electrogenic sarcolemmal ion currents may control the amplitude and phase of beat-to-beat alternans of membrane potential (Vm). However, experimental evidence for the mechanism by which alternans of calcium transients produces alternation of Vm (Vm-ALT) is lacking. Objective We sought to provide experimental evidence that Ca-to-Vm coupling during alternans is determined by the balanced influence of two Ca-sensitive electrogenic sarcolemmal ionic currents, INCX and ICa. Methods and Results Vm-ALT and Ca-ALT were measured simultaneously from isolated guinea pig myocytes (n=41) using perforated patch and Indo-1AM fluorescence, respectively. There were three study groups: 1) Control, 2) INCX predominance created by adenoviral-induced NCX overexpression, and 3) ICa predominance created by INCX inhibition (SEA-0400) or enhanced ICa (As2O3). During alternans, 14 of 14 control myocytes demonstrated positive Ca-to-Vm coupling, consistent with INCX, but not ICa as the major electrogenic current in modulating action potential duration. Positive Ca-to-Vm coupling was maintained during INCX predominance in 8 of 8 experiments with concurrent increase in Ca-to-Vm gain (p<0.05), reaffirming the role of increased forward mode electrogenic INCX. Conversely, ICa predominance produced negative Ca-to-Vm coupling in 14 of 19 myocytes (p<0.05) and decreased Ca-to-Vm gain compared to control (p<0.05). Furthermore, computer simulation demonstrated that Ca-to-Vm coupling changes from negative to positive was due to a shift from ICa to INCX predominance with increasing pacing rate. Conclusion These data provide the first direct experimental evidence that coupling in phase and magnitude of Ca-ALT to Vm-ALT is strongly determined by relative balance of prominence of INCX versus ICa currents.

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Section: Discussionmentioning

confidence: 99%

New experimental evidence for mechanism of arrhythmogenic membrane potential alternans based on balance of electrogenic INCX/ICa currents

et al. 2012

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“…If the slow shortening of the action potential is not due to changes of extracellular potassium then a likely alternative is that changes of intracellular ions, particularly sodium and calcium, are involved. Work in many cardiac tissues has shown that increasing the frequency of stimulation increases the intracellular sodium concentration, [Na + ] i (Kaila & Vaughan‐Jones, 1985; Boyett et al 1987; Harrison et al 1992; Harrison & Boyett, 1995). This increase of [Na + ] i will (via NCX) increase intracellular calcium concentration ([Ca 2+ ] i ), and we must therefore consider effects mediated by changes of both [Ca 2+ ] i and [Na + ] i .…”

Section: The Mechanism Of the Slow Changes Of Apdmentioning

confidence: 99%

“…Simulations (Faber & Rudy, 2000) suggest that this increased outward NCX current contributes to the shortening of the APD, although to the best of our knowledge there have been no experimental tests of this. One study has shown that increased stimulation of guinea‐pig ventricular myocytes results in increased outward NCX current accompanied by an increase of [Na + ] i (Harrison & Boyett, 1995). That study speculated that this current could contribute to the slow changes of APD, but no measurements of action potentials were made to demonstrate causality.…”

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The mechanism and significance of the slow changes of ventricular action potential duration following a change of heart rate

Eisner

Dibb

Trafford

2009

Experimental Physiology

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This article reviews the effects of changes of heart rate on the ventricular action potential duration. These can be divided into short term (fractions of a second), resulting from the kinetics of recovery of membrane currents, through to long term (up to days), resulting from changes of protein expression. We concentrate on the medium-term changes (time course of the order of 100 s). These medium-term changes occur in isolated tissues and in the intact human heart. They may protect against cardiac arrhythmias. Finally, we discuss the cellular mechanisms responsible for these changes. The action potential duration (APD)It is essential that the cardiac action potential duration (APD) is regulated precisely. The APD determines the refractory period of the heart and if it becomes too short premature re-excitation can occur, leading to such arrhythmogenic phenomena as re-entry. Much evidence has shown that conditions, such as heart failure and ischaemia, where APD varies between different regions of the ventricle, are particularly dangerous in terms of inducing arrhythmias. In contrast, excessive prolongation of the APD is also dangerous. This can result in early after-depolarizations and arrhythmias seen on the ECG as 'torsades de pointes' . Indeed, prolongation of the APD (or QT interval) and perceived pro-arrhythmic risk has led to the withdrawal of many, otherwise potentially useful, drugs (Fenichel et al. 2004). The APD is not uniform throughout the ventricle; differences of APD either across the ventricular wall or between base and apex are thought to be responsible for the fact that in many leads the T wave of the ECG has the same polarity as the QRS complex. Effects of heart rate on APDThe APD varies with heart rate. Indeed, in order to increase the heart rate, it is essential that the APD and therefore the refractory period decrease. The relationship between heart rate and APD is well appreciated in clinical work, and the QT interval is often corrected for heart rate (QT c ; Luo et al. 2004). The effects on APD of a sudden change of heart rate develop over a variety of time courses. For the purpose of this review we will focus on three phases, as follows: (1) an early phase (milliseconds to hundreds of milliseconds), due to changes of voltage-and timedependent currents; (2) a slower phase, occurring over a minute or so; and (3) a very slow phase that develops over hours to days, the so-called cardiac memory. The first two phases recorded from a human heart are shown in Fig. 1 (Franz et al. 1988).The effects of rate on APD or QT interval result from a number of different mechanisms. While the main focus of this article is the slower phase, it is important to begin by briefly reviewing the early phase. Short-term effects due to incomplete recovery of ionic currentsChanges in several ionic currents contribute to the early phase of action potential shortening on increasing stimulation frequency. The short-term effects are best seen by interpolating an extra stimulus as shown in Fig. 2 (Bass, 1975). Here acti...

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“…(1993). The same mechanism appears to be involved in part in the rate‐dependent increase in contraction (Harrison & Boyett 1995). This mechanism is based on the model of Harrison et al .…”

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confidence: 97%

Potentiation of the contraction following a prolonged depolarization in isolated ferret myocardium

Arlock

Wohlfart

Noble

1998

Acta Physiologica Scandinavica

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The contractile force was studied in ferret papillary muscles during voltage clamp depolarizations, using the single sucrose gap method. Prolongation of a test depolarization within a train produced potentiation of the following contraction. The effects of varied duration and membrane potential of the test depolarization upon the potentiated force of the following beat were studied. We assumed that force of a beat was an index of calcium entry on the previous depolarization. The relationship between the peak contractile force of the following potentiated beat and the systolic membrane potential of the test depolarization revealed an equilibrium around -18 mV. This was manifest after 100 ms of no effect. Positive potentials caused potentiation of force of the following beat; negative potentials caused suppression of force of the following beat. Calcium entry, if carried by an electrogenic exchange mechanism, would be revealed as a membrane current developing after 100 ms. Membrane current at these times was always outward. When the duration of the test depolarization was prolonged, outward current prior to repolarisation progressively increased. When the duration of the test depolarization was held constant, outward current was varied by variation in membrane potential. Force of the following beat was proportional to the test clamp membrane potential. The potentiation of the contraction following a prolonged depolarization was abolished by substituting 75% of the sodium in the perfusion medium with lithium. These results are compatible with the hypothesis that potentiation of force following a prolonged depolarization is derived from calcium entry into myocardial cells by reversed sodium-calcium exchange.

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The role of the Na(+)‐Ca2+ exchanger in the rate‐dependent increase in contraction in guinea‐pig ventricular myocytes.

Cited by 31 publications

References 24 publications

New experimental evidence for mechanism of arrhythmogenic membrane potential alternans based on balance of electrogenic INCX/ICa currents

New experimental evidence for mechanism of arrhythmogenic membrane potential alternans based on balance of electrogenic INCX/ICa currents

The mechanism and significance of the slow changes of ventricular action potential duration following a change of heart rate

Potentiation of the contraction following a prolonged depolarization in isolated ferret myocardium

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