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1: Circ Res. 2006 May 26;98(10):1299-305. Epub 2006 Apr 13.
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Reducing ryanodine receptor open probability as a means to abolish spontaneous Ca2+ release and increase Ca2+ transient amplitude in adult ventricular myocytes.

Venetucci LA, Trafford AW, Díaz ME, O'Neill SC, Eisner DA.

Unit of Cardiac Physiology, University of Manchester, United Kingdom.

The aim of this work was to investigate whether it is possible to remove arrhythmogenic Ca2+ release from the sarcoplasmic reticulum that occurs in calcium overload without compromising normal systolic release. Exposure of rat ventricular myocytes to isoproterenol (1 micromol/L) resulted in an increased amplitude of the systolic Ca2+ transient and the appearance of waves of diastolic Ca2+ release. Application of tetracaine (25 to 50 micromol/L) decreased the frequency or abolished the diastolic Ca2+ release. This was accompanied by an increase in the amplitude of the systolic Ca2+ transient. Cellular Ca2+ flux balance was investigated by integrating Ca2+ entry (on the L-type Ca2+ current) and efflux (on Na-Ca2+ exchange). Isoproterenol increased Ca2+ influx but failed to increase Ca2+ efflux during systole (because of the abbreviation of the duration of the Ca2+ transient). To match this increased influx the bulk of Ca2+ efflux occurred via Na-Ca2+ exchange during a diastolic Ca2+ wave. Subsequent application of tetracaine increased systolic Ca2+ efflux and abolished the diastolic efflux. The increase of systolic efflux in tetracaine resulted from both increased amplitude and duration of the systolic Ca2+ transient. In the presence of isoproterenol, those Ca2+ transients preceded by diastolic release were smaller than those where no diastolic release had occurred. When tetracaine was added, the amplitude of the Ca2+ transient was similar to those in isoproterenol with no diastolic release and larger than those preceded by diastolic release. We conclude that tetracaine increases the amplitude of the systolic Ca2+ transient by removing the inhibitory effect of diastolic Ca2+ release.

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PMID: 16614307 [PubMed - indexed for MEDLINE]