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Depressed Ryanodine Receptor Activity Increases Variability and Duration of the Systolic Ca²⁺ Transient in Rat Ventricular Myocytes

From the Unit of Cardiac Physiology, University of Manchester, Manchester, UK.

Correspondence to Stephen O’Neill, PhD, University of Manchester, The Unit of Cardiac Physiology, Dept of Medicine, 1.524 Stopford Bldg, Oxford Road, Manchester, M13 9PT, UK. E-mail stephen.c.o'neill{at}man.ac.uk

Sarcoplasmic reticulum (SR) Ca²⁺ release, through the ryanodine receptor (RyR), is essential for the systolic Ca²⁺ transient and thus the cardiac contractile function. The aim of this study was to examine the effects on the spatial organization of the systolic Ca²⁺ transient of depressing RyR open probability (P_o) with tetracaine or intracellular acidification. Voltage-clamped, fluo-3–loaded myocytes were studied using confocal microscopy. Depressing RyR P_o increased the variability of the Ca²⁺ transient amplitude between different regions of the cell. This variability often produced alternans with a region producing large and small transients alternately. In addition, the raising phase of the Ca²⁺ transient became biphasic. The initial phase was constant but the second was variable and propagated as a wave through part of the cell. That both phases involved SR Ca²⁺ release was shown by their reduction by caffeine. Regional [Ca²⁺]_i alternans was accompanied by a much smaller degree of alternans at the whole cell level. We suggest that, in tetracaine or acidosis, the initial phase of the Ca²⁺ transient results from Ca²⁺ release via RyRs directly activated by adjacent L-type Ca²⁺ channels. At some sites, this will activate neighboring RyRs and a Ca²⁺ wave will propagate via activation of other RyRs. This work is the first demonstration that decreased RyR P_o alone can produce disarray of the Ca²⁺ release process and initiate alternans.

Key Words: calcium • ryanodine receptor • alternans

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