Ranolazine antagonizes the effects of increased late sodium current on intracellular calcium cycling in rat isolated intact heart

J. Andrew Wasserstrom, Rohan Sharma, Matthew J. O'Toole, Jiabo Zheng, James E. Kelly, John Shryock, Luiz Belardinelli, Gary L. Aistrup

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Pathological conditions, including ischemia and heart failure, are associated with altered sodium channel function and increased late sodium current (INa,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 INa,L on intracellular calcium cycling in rat isolated hearts. Cardiac contraction was abolished using paralytic agents. Ranolazine (RAN) was used to inhibit late INa. 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 μM). Most importantly, the increased vulnerability of the heart to the development of calcium alternans during rapid pacing was reversed or prevented by 10 μM RAN. These results suggest that enhancement of INa,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.

Original languageEnglish (US)
Pages (from-to)382-391
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume331
Issue number2
DOIs
StatePublished - Nov 1 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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