title: Reducing ryanodine receptor open probability as a means to abolish spontaneous Ca2+ release and increase Ca2+ transient amplitude in adult ventricular myocytes.
abstract: 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.
authors.affiliation: Unit of Cardiac Physiology, University of Manchester, United Kingdom.
authors.forename: L A
authors.initials: LA
authors.lastname: Venetucci
authors.forename: A W
authors.initials: AW
authors.lastname: Trafford
authors.forename: M E
authors.initials: ME
authors.lastname: Díaz
authors.forename: S C
authors.initials: SC
authors.lastname: O'Neill
authors.forename: D A
authors.initials: DA
authors.lastname: Eisner
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology; D003971:Diastole; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism; D013599:Systole; D013748:Tetracaine / Q000494:pharmacology
chemical_list: D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D019837:Ryanodine Receptor Calcium Release Channel; D013748:Tetracaine; D007545:Isoproterenol; D002118:Calcium