Published online before print April 13, 2006, doi: 10.1161/01.RES.0000222000.35500.65
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Submitted on February 17, 2006
Revised on March 29, 2006
Accepted on March 30, 2006
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 *;
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.
* To whom correspondence should be addressed. E-mail: lavenetucci{at}yahoo.co.uk.
The aim of this work was to investigate whether it is possible to remove arrhythmogenic Ca 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 Ca transient and the appearance of waves of diastolic Ca release. Application of tetracaine (25 to 50 µmol/L) decreased the frequency or abolished the diastolic Ca release. This was accompanied by an increase in the amplitude of the systolic Ca transient. Cellular Ca flux balance was investigated by integrating Ca entry (on the L-type Ca current) and efflux (on Na-Ca exchange). Isoproterenol increased Ca influx but failed to increase Ca efflux during systole (because of the abbreviation of the duration of the Ca transient). To match this increased influx the bulk of Ca efflux occurred via Na-Ca exchange during a diastolic Ca wave. Subsequent application of tetracaine increased systolic Ca efflux and abolished the diastolic efflux. The increase of systolic efflux in tetracaine resulted from both increased amplitude and duration of the systolic Ca transient. In the presence of isoproterenol, those Ca transients preceded by diastolic release were smaller than those where no diastolic release had occurred. When tetracaine was added, the amplitude of the Ca 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 Ca transient by removing the inhibitory effect of diastolic Ca release.
Key words: spontaneous release • calcium • sarcoplasmic reticulum • arrhythmias
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