Slowly Inactivating Component of Sodium Current in Ventricular Myocytes is Decreased by Diabetes and Partially Inhibited by Known Na+-H+Exchange Blockers

Chattou, Soad; Coulombe, Alain; Diacono, J; Grand, Bruno Le; John, Gareth W.; Feuvray, D.

doi:10.1006/jmcc.2000.1151

Cited by 33 publications

(24 citation statements)

References 37 publications

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“…f Group results showing the effects of amiloride, TTX, and zoniporide on I Na,P , TTX set to 100%. Double asterisk means significantly different to TTX, p<0.005. n=7 for TTX, n=4 for amiloride and n=6 for zoniporide fined by the reduction in current caused by TTX [8,32]. In Fig.…”

Section: Measurements Of Na + Channel Activitymentioning

confidence: 95%

“…(3) Chattou et al [8] have shown that NHE1 inhibitors (ethyl-isopropyl amiloride, HOE 694 and cariporide) inhibited I Na,P providing a potential alternative mechanism of action. (4) Some studies have failed to show any effect of NHE1 inhibitors on [Na + ] i during ischemia although the inhibitors produced cardioprotection, prevented the rise of [Na + ] i on reperfusion and slowed the recovery of pH i during reperfusion [45].…”

Section: Introductionmentioning

confidence: 99%

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The rise of [Na+]i during ischemia and reperfusion in the rat heart—underlying mechanisms

Williams

Xiao

et al. 2007

Pflugers Arch - Eur J Physiol

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Intracellular Na(+) concentration ([Na(+)](i)) rises in the heart during ischemia, and on reperfusion, there is a transient rise followed by a return toward control. These changes in [Na(+)](i) contribute to ischemic and reperfusion damage through their effects on Ca(2+) overload. Part of the rise of [Na(+)](i) during ischemia may be caused by increased activity of the cardiac Na(+)/H(+) exchanger (NHE1), activated by the ischemic rise in [H(+)](i). In support of this view, NHE1 inhibitors reduce the [Na(+)](i) rise during ischemia. Another possibility is that the rise of [Na(+)](i) during ischemia is caused by Na(+) influx through channels. We have reexamined these issues by use of two different NHE1 inhibitors, amiloride, and zoniporide, in addition to tetrodotoxin (TTX), which blocks voltage-sensitive Na(+) channels. All three drugs produced cardioprotection after ischemia, but amiloride (100 microM) and TTX (300 nM) prevented the rise in [Na(+)](i) during ischemia, whereas zoniporide (100 nM) did not. Both amiloride and zoniporide prevented the rise of [Na(+)](i) on reperfusion, whereas TTX was without effect. In an attempt to explain these differences, we measured the ability of the three drugs to block Na(+) currents. At the concentrations used, TTX reduced the transient Na(+) current (I (Na)) by 11 +/- 2% while amiloride and zoniporide were without effect. In contrast, TTX largely eliminated the persistent Na(+) current (I (Na,P)) and amiloride was equally effective, whereas zoniporide had a substantially smaller effect reducing I (Na,P) to 41 +/- 8%. These results suggest that part of the effect of NHE1 inhibitors on the [Na(+)](i) during ischemia is by blockade of I (Na,P). The fact that a low concentration of TTX eliminated the rise of [Na(+)](i) during ischemia suggests that I (Na,P) is a major source of Na(+) influx in this model of ischemia.

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Section: Measurements Of Na + Channel Activitymentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

The rise of [Na+]i during ischemia and reperfusion in the rat heart—underlying mechanisms

Williams

Xiao

et al. 2007

Pflugers Arch - Eur J Physiol

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“…It has also been identified in VCs of dogs (Maltsev et al, 2007;Undrovinas et al, 2006;Undrovinas et al, 1999;Zygmunt et al, 2001), guinea pigs La et al, 2006;Sakmann et al, 2000), rabbits (Wu et al, 2006) and rats (Chattou et al, 2000).…”

Section: Biophysical Characteristics Of I Nalmentioning

confidence: 99%

“…Experimentally, LPC causes depolarization, reduction of the maximal upstroke velocity of AP, sustained abnormal rhythmic activity in Purkinje fibers, and delayed afterpotentials (DADs) in isolated tissue (Arnsdorf and Sawicki, 1981;Corr et al, 1987). The mechanisms of the LPC effects include modifications of Na + current (Burnashev et al, 1991;Burnashev et al, 1989;Chattou et al, 2000;Shander et al, 1996;Undrovinas et al, 1992). Such modifications account for a reduction of I NaT and an emergence of late openings that produce a sustained Na + current.…”

Section: Modulation Of I Nal By Lysophosphatidylcholine (Lpc)mentioning

confidence: 99%

Late sodium current in failing heart: Friend or foe?

Maltsev

Undrovinas

2008

Progress in Biophysics and Molecular Biology

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Most cardiac Na + channels open transiently upon membrane depolarization and then are quickly inactivated. However, some channels remain active, carrying the so-called persistent or late Na + current (I NaL ) throughout the action potential (AP) plateau. Experimental data and the results of numerical modeling accumulated over the past decade show the emerging importance of this late current component for the function of both normal and failing myocardium. I NaL is produced by special gating modes of the cardiac-specific Na + channel isoform. Heart failure (HF) slows channel gating and increases I NaL , but HF-specific Na + channel isoform underlying these changes has not been found. Na + channels represent a multi-protein complex and its activity is determined not only by the pore-forming α subunit but also by its auxiliary β subunits, cytoskeleton, calmodulin, regulatory kinases and phosphatases, and trafficking proteins. Disruption of the integrity of this protein complex may lead to alterations of I NaL in pathological conditions. Increased I NaL and the corresponding Na + flux in failing myocardium contribute to abnormal repolarization and an increased cell Ca 2+ load. Interventions designed to correct I NaL rescue normal repolarization and improve Ca 2+ handling and contractility of the failing cardiomyocytes. This review considers 1) quantitative integration of I NaL into the established electrophysiological and Ca 2+ regulatory mechanisms in normal and failing cardiomyocytes and 2) a new therapeutic strategy utilizing a selective inhibition of I NaL to target both arrhythmias and impaired contractility in HF.

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“…Using almost the same rabbit HF model we used, Baartscheer et al (2) showed that the elevated [Na + ] i in HF was cariporide-sensitive, suggesting an important role for NHE. Since NHE was also upregulated in HF, this seems plausible, but the concentrations of cariporide used also inhibit slowly inactivating I Na (11), leaving the role of NHE in [Na] i elevation in HF somewhat equivocal. The role of slowly inactivating I Na also merits further exploration, because this current can contribute to AP prolongation and triggered arrhythmias (see below).…”

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confidence: 99%

Altered Cardiac Myocyte Ca Regulation In Heart Failure

2006

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Ca removal during relaxation is mainly due to SR CaATPase and NCX (as above). In HF, there is typically a downregulation of SR Ca-ATPase and upregulation of NCX function (36,42,43). Both of these effects tend to shift Ca out of the cell and reduce SR Ca content (see below). That is, during [Ca] i decline, NCX and SR CaATPase compete for Ca, and the more that is extruded from the cell (by NCX) the less SR Ca-ATPase can take Ca is critical in both the electrical and mechanical properties of cardiac myocytes, and much is known about ionic currents and the normal excitation-contraction coupling process. In heart failure, there are significant alterations in how myocyte Ca is regulated, and these alterations are critical in dictating both contractile dysfunction and certain cardiac arrhythmias that are characteristic of heart failure.P PH HY YS SI IO OL LO OG GY Y 2 21 1: : 3 38 80 0--3 38 87 7, , 2

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Slowly Inactivating Component of Sodium Current in Ventricular Myocytes is Decreased by Diabetes and Partially Inhibited by Known Na+-H+Exchange Blockers

Cited by 33 publications

References 37 publications

The rise of [Na+]i during ischemia and reperfusion in the rat heart—underlying mechanisms

The rise of [Na+]i during ischemia and reperfusion in the rat heart—underlying mechanisms

Late sodium current in failing heart: Friend or foe?

Altered Cardiac Myocyte Ca Regulation In Heart Failure

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