Multiple Defects in Intracellular Calcium Cycling in Whole Failing Rat Heart

Wasserstrom, J. Andrew; Sharma, Rohan; Kapur, Sunil; Kelly, James E.; Kadish, Alan H.; Balke, C. William; Aistrup, Gary L.

doi:10.1161/circheartfailure.108.811539

Cited by 43 publications

(51 citation statements)

References 31 publications

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“…An interesting implication of these results is that RAN could be antiarrhythmic in the settings of ischemia and congestive heart failure where the vulnerability to calcium alternans is also increased (Kapur et al, 2009a;Wasserstrom et al, 2009;Wilson et al, 2009) and where enhanced late I Na has been demonstrated (Maltsev et al, 2001(Maltsev et al, , 2007Undrovinas et al, 2002Undrovinas et al, , 2006Valdivia et al, 2005), although a link between these two effects remains to be investigated. Finally, it is important to note that RAN also blocks human ether a-go-go-related gene channels and thus might induce some of its electrophysiological actions independently from the blockade of I Na,L .…”

Section: Ran Blocks Effects Of Late I Na On Cardiac Calcium Cycling 389mentioning

confidence: 96%

Ranolazine Antagonizes the Effects of Increased Late Sodium Current on Intracellular Calcium Cycling in Rat Isolated Intact Heart

Wasserstrom

Sharma²,

O'Toole³

et al. 2009

J Pharmacol Exp Ther

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Pathological conditions, including ischemia and heart failure, are associated with altered sodium channel function and increased late sodium current (I Na,L ), leading to prolonged action potential duration, increased intracellular sodium and calcium concentrations, and arrhythmias. We used anemone toxin (ATX)-II to study the effects of increasing I Na,L on intracellular calcium cycling in rat isolated hearts. Cardiac contraction was abolished using paralytic agents. Ranolazine (RAN) was used to inhibit late I Na . Hearts were loaded with fluo-4-acetoxymethyl ester, and myocyte intracellular calcium transients (CaTs) were measured using laser scanning confocal microscopy. ATX (1 nM) prolonged CaT duration at 50% recovery in hearts paced at a basal rate of 2 Hz and increased the sensitivity of the heart to the development of calcium alternans caused by fast pacing.ATX increased the time required for recovery of CaT amplitude following a previous beat, and ATX induced spontaneous calcium release waves during rapid pacing of the heart. ATX prolonged the duration of repolarization from the initiation of the activation to terminal repolarization in the pseudo-electrocardiogram. All actions of ATX were both reversed and prevented by subsequent or prior exposure, respectively, of hearts to RAN (10 M). Most importantly, the increased vulnerability of the heart to the development of calcium alternans during rapid pacing was reversed or prevented by 10 M RAN. These results suggest that enhancement of I Na,L alters calcium cycling. Reduction by RAN of I Na,L -induced dysregulation of calcium cycling could contribute to the antiarrhythmic actions of this agent in both reentrant and triggered arrhythmias.The pathology of calcium overload in the heart includes both mechanical and electrical dysfunction (Vassalle and Lin, 2004). At slow rates of pacing, the reopening of calcium channels late in the action potential plateau may facilitate the occurrence of early afterdepolarizations, whereas at fast rates, abnormalities of calcium handling and intracellular calcium transients become manifest, including spontaneous release of calcium from the sarcoplasmic reticulum (SR), transient inward current, delayed afterdepolarizations and aftercontractions, calcium alternans, and triggered arrhythmic activity. There is growing evidence that rate-dependent alternations in SR calcium release (i.e., calcium alternans) contribute to action potential duration alternans (Walker and Rosenbaum, 2003;Pruvot et al., 2004;Wasserstrom et al., 2008; Kapur et al., 2009a,b), which may be responsible for T-wave alternans, the development of repolarization gradients, and re-entrant arrhythmias.As a consequence of Na,Ca-exchange, an increase of sodium influx can lead to increases of calcium influx and intracellular calcium concentration and calcium overload in the heart (Verdonck et al., 1991;Verdonck et al., 1993). Cardiac sodium channels that fail to inactivate quickly after a brief This work was supported by a grant from Gilead Sciences, Inc. Ar...

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Section: Ran Blocks Effects Of Late I Na On Cardiac Calcium Cycling 389mentioning

confidence: 96%

Ranolazine Antagonizes the Effects of Increased Late Sodium Current on Intracellular Calcium Cycling in Rat Isolated Intact Heart

Wasserstrom

Sharma²,

O'Toole³

et al. 2009

J Pharmacol Exp Ther

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“…Furthermore, RyR2 R4496C hearts showed significantly lower alternans ratio and alternans duration at each stimulation frequency between 10-14 Hz (Fig.2C, D (40,55,57). It is thought that SCR necessitates and facilitates the occurrence of Ca 2+ alternans (25,28,38,(41)(42)(43)(44)(45)(46). Hence, it is of interest to determine whether SCR is involved in the occurrence of Ca 2+ alternans in intact working RyR2 R4496C mutant hearts.…”

mentioning

confidence: 96%

The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2+-ATPase, is a major determinant of Ca2+ alternans in intact mouse hearts

Sun

Wei

Zhong

et al. 2018

Journal of Biological Chemistry

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“…[7][8][9][10][11] There are multiple problems that could lead to Ca 2ϩ cycling defects at the level of Ca 2ϩ release from the sarcoplasmic reticulum (SR), 9 but one of the first recognized and among the most important was a decrease in expression of the Ca 2ϩ -sensitive ATPase in the SR. This protein is responsible for Ca 2ϩ reuptake into SR and thus serves as the main mechanism for clearance of Ca 2ϩ from the cytoplasm, which then terminates systole and initiates diastole.…”

Section: How Does Calcium Dysregulation Results In Ventricular Arrhythmentioning

confidence: 99%

SERCA2a Gene Therapy for the Prevention of Sudden Cardiac Death

Shah

Wasserstrom

2012

Circulation

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Multiple Defects in Intracellular Calcium Cycling in Whole Failing Rat Heart

Cited by 43 publications

References 31 publications

Ranolazine Antagonizes the Effects of Increased Late Sodium Current on Intracellular Calcium Cycling in Rat Isolated Intact Heart

Ranolazine Antagonizes the Effects of Increased Late Sodium Current on Intracellular Calcium Cycling in Rat Isolated Intact Heart

The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2+-ATPase, is a major determinant of Ca2+ alternans in intact mouse hearts

SERCA2a Gene Therapy for the Prevention of Sudden Cardiac Death

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