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(Circulation Research. 2006;98:1299.)
© 2006 American Heart Association, Inc.

Cellular Biology

Reducing Ryanodine Receptor Open Probability as a Means to Abolish Spontaneous Ca²⁺ Release and Increase Ca²⁺ Transient Amplitude in Adult Ventricular Myocytes

L.A. Venetucci, A.W. Trafford, M.E. Díaz, S.C. O’Neill, D.A. Eisner

From the Unit of Cardiac Physiology, University of Manchester, United Kingdom. Present address for M.E.D.: Veterinary Biomedical Sciences, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, United Kingdom.

Correspondence to D.A. Eisner, Unit of Cardiac Physiology, 3.18 Core Technology Facility, 46 Grafton St, Manchester M13 9PT, United Kingdom. E-mail eisner{at}man.ac.uk

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 µmol/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 µmol/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.

Key Words: spontaneous release • calcium • sarcoplasmic reticulum • arrhythmias

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