ASSA14-03-46 Inhibition of late sodium current reduces the reverse rate dependence of action potential duration prolongation induced by L-type calcium channel activator

Aging hearts have prolonged QT interval and are vulnerable to oxidative stress. Because the QT interval indirectly reflects the action potential duration (APD), we examined the hypotheses that 1) the APD of ventricular myocytes increases with age; 2) the age-related prolongation of APD is due to an enhancement of basal late Na+ current ( INaL); and 3) inhibition of INaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H2O2). Experiments were performed on ventricular myocytes isolated from (young) 1-mo- and (old) 1-yr-old guinea pigs (GPs). The APD of myocytes from old GPs was significantly longer than that from young GPs and was shortened by the INaL inhibitors GS967 and tetrodotoxin. The magnitude of INaL was significantly larger in myocytes from old than from young GPs. The CaMKII inhibitors KN-93 and AIP and the NaV1.5-channel blocker methanethiosulfonate ethylammonium blocked the INaL. There were no significant differences between myocytes from young and old GPs in L-type Ca2+ current and the rapidly and slowly activating delayed rectifier K+ currents, although the inward rectifier K+ current was slightly decreased in myocytes from old GPs. H2O2 induced more early afterdepolarizations in myocytes from old than from young GPs. The effect of H2O2 was attenuated by GS967. The results suggest that 1) the APD of myocytes from old GPs is prolonged, 2) a CaMKII-mediated increase in NaV1.5-channel INaL is responsible for the prolongation of APD, and 3) inhibition of INaL may be beneficial for maintaining electrical stability under oxidative stress in myocytes of old GPs. NEW & NOTEWORTHY The action potential duration is significantly longer in ventricular myocytes from old than from young guinea pigs, which may explain, at the cellular level, the increase in QT interval with age. A CaMKII-mediated enhancement of NaV1.5-channel late current is responsible for the age-related prolongation of action potential duration. The enhanced basal late sodium current may predispose cardiac myocytes of old animals to oxidative stress and arrhythmogenesis.

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1110-213 Ranolazine attenuates increased variability of action potential duration and after depolarizations caused by augmentation of late sodium current

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(04)90539-6 ◽

2004 ◽

Vol 43 (5) ◽

pp. A128

Author(s):

Yejia Song ◽

Lin Wu ◽

John C Shryock ◽

Luiz Belardinelli

Keyword(s):

Action Potential ◽

Action Potential Duration ◽

Sodium Current ◽

Late Sodium Current

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The non-dihydropyridine L-type voltage-sensitive calcium channel activator FPL 64176 enhances K+-evoked efflux of [3H]norepinephrine from rat neocortical slices

Neuroscience Letters ◽

10.1016/0304-3940(93)90433-l ◽

1993 ◽

Vol 156 (1-2) ◽

pp. 35-38 ◽

Cited By ~ 9

Author(s):

T. Ginap ◽

D.J. Dooley ◽

T.J. Feuerstein

Keyword(s):

Calcium Channel ◽

Calcium Channel Activator ◽

Channel Activator

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Cytosolic magnesium modulates calcium channel activity in mammalian ventricular cells

AJP Cell Physiology ◽

10.1152/ajpcell.1989.256.2.c452 ◽

1989 ◽

Vol 256 (2) ◽

pp. C452-C455 ◽

Cited By ~ 80

Author(s):

Z. S. Agus ◽

E. Kelepouris ◽

I. Dukes ◽

M. Morad

Keyword(s):

Action Potential ◽

Calcium Channel ◽

Action Potential Duration ◽

Calcium Current ◽

Concentration Addition ◽

High Threshold ◽

Channel Activity ◽

Mean Values ◽

Ventricular Cells ◽

In Cells

The effect of cytosolic free Mg2+ concentration on the regulation of myocardial function was studied by dialyzing isolated guinea pig ventricular myocytes with different internal Mg2+ concentrations [( Mg2+]i). We found that elevation of [Mg2+]i shortened the action potential and suppressed the Ca2+ current. Mean values recorded for action potential duration in cells dialyzed with solutions containing 0, 1.3, and 9.4 mM Mg2+ were 620 +/- 40, 400 +/- 25, and 60 +/- 10, respectively. The suppressive effect of [Mg2+]i on the action potential duration correlated significantly with the suppressive effects of [Mg2+]i on the Ca2+ current. In cells dialyzed with nominally zero Mg2+, calcium current was prominent (3.5 +/- 0.58 nA). At [Mg2+]i of 1.4 mM, calcium current was significantly smaller than in zero [Mg2+]i and was almost completely inhibited by dialysis of the cell with 9.4 mM Mg2+. The Mg2+-induced block of the Ca2+ current was due to steady-state inactivation of the high threshold calcium channel. The block was observed in the presence or absence of adenosine 3',5'-cylic monophosphate and was not reversed by elevation of external Ca2+ concentration, addition of adrenaline, or large negative potentials. These data suggest that cytosolic Mg2+ regulates Ca2+ channel activity by a novel mechanism, unrelated to its effect as a blocking particle of the open channel.

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