Abstract
Subcellular Ca$^2+$ signalling during normal excitation-contraction
(E-C) coupling and during Ca$^2+$ alternans was studied in atrial
myocytes using fast confocal microscopy and measurement of Ca$^2+$
currents (I(Ca)). Ca$^2+$ alternans, a beat-to-beat alternation
in the amplitude of the Ca$^2+$(i) transient, causes electromechanical
alternans, which has been implicated in the generation of cardiac
fibrillation and sudden cardiac death. Cat atrial myocytes lack transverse
tubules and contain sarcoplasmic reticulum (SR) of the junctional
(j-SR) and non-junctional (nj-SR) types, both of which have ryanodine-receptor
calcium release channels. During E-C coupling, Ca$^2+$ entering
through voltage-gated membrane Ca$^2+$ channels (I(Ca)) triggers
Ca$^2+$ release at discrete peripheral j-SR release sites. The
discrete Ca$^2+$ spark-like increases of Ca$^2+$(i) then
fuse into a peripheral 'ring' of elevated Ca$^2+$(i), followed
by propagation (via calcium-induced Ca$^2+$ release, CICR) to
the cell centre, resulting in contraction. Interrupting I(Ca) instantaneously
terminates j-SR Ca$^2+$ release, whereas nj-SR Ca$^2+$ release
continues. Increasing the stimulation frequency or inhibition of
glycolysis elicits Ca$^2+$ alternans. The spatiotemporal Ca$^2+$(i)
pattern during alternans shows marked subcellular heterogeneities
including longitudinal and transverse gradients of Ca$^2+$(i)
and neighbouring subcellular regions alternating out of phase. Moreover,
focal inhibition of glycolysis causes spatially restricted Ca$^2+$
alternans, further emphasising the local character of this phenomenon.
When two adjacent regions within a myocyte alternate out of phase,
delayed propagating Ca$^2+$ waves develop at their border. In
conclusion, the results demonstrate that (1) during normal E-C coupling
the atrial Ca$^2+$(i) transient is the result of the spatiotemporal
summation of Ca$^2+$ release from individual release sites of
the peripheral j-SR and the central nj-SR, activated in a centripetal
fashion by CICR via I(Ca) and Ca$^2+$ release from j-SR, respectively,
(2) Ca$^2+$ alternans is caused by subcellular alterations of
SR Ca$^2+$ release mediated, at least in part, by local inhibition
of energy metabolism, and (3) the generation of arrhythmogenic Ca$^2+$
waves resulting from heterogeneities in subcellular Ca$^2+$ alternans
may constitute a novel mechanism for the development of cardiac dysrhythmias.
Description
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