Abstract
Spontaneous, submembrane local Ca2+ releases (LCRs) generated by the sarcoplasmic reticulum in sinoatrial nodal cells, the cells of the primary cardiac pacemaker, activate inward Na+/Ca2+-exchange current to accelerate the diastolic depolarization rate, and therefore to impact on cycle length. Since LCRs are generated by Ca2+ release channel (i.e. ryanodine receptor) openings, they exhibit a degree of stochastic behavior, manifested as notable cycle-to-cycle variations in the time of their occurrence.AimThe present study tested whether variation in LCR periodicity contributes to intrinsic (beat-to-beat) cycle length variability in single sinoatrial nodal cells.MethodsWe imaged single rabbit sinoatrial nodal cells using a 2D-camera to capture LCRs over the entire cell, and, in selected cells, simultaneously measured action potentials by perforated patch clamp.ResultsLCRs begin to occur on the descending part of the action potential-induced whole-cell Ca2+ transient, at about the time of the maximum diastolic potential. Shortly after the maximum diastolic potential (mean 54±7.7 ms, n = 14), the ensemble of waxing LCR activity converts the decay of the global Ca2+ transient into a rise, resulting in a late, whole-cell diastolic Ca2+ elevation, accompanied by a notable acceleration in diastolic depolarization rate. On average, cells (n = 9) generate 13.2±3.7 LCRs per cycle (mean±SEM), varying in size (7.1±4.2 µm) and duration (44.2±27.1 ms), with both size and duration being greater for later-occurring LCRs. While the timing of each LCR occurrence also varies, the LCR period (i.e. the time from the preceding Ca2+ transient peak to an LCR’s subsequent occurrence) averaged for all LCRs in a given cycle closely predicts the time of occurrence of the next action potential, i.e. the cycle length.ConclusionIntrinsic cycle length variability in single sinoatrial nodal cells is linked to beat-to-beat variations in the average period of individual LCRs each cycle.
Highlights
The heart rate of healthy subjects exhibits complex variability that is not well understood
Intrinsic cycle length variability in single sinoatrial nodal cells is linked to beat-to-beat variations in the average period of individual local Ca2+ releases (LCRs) each cycle
Some LCRs terminate and disappear, while others continue to grow in size, merging into the second phase of Ca2+ release, observed as a strong, high-amplitude global cytosolic Ca2+ transient (CaT) induced by the occurrence of the subsequent action potential (AP)
Summary
The heart rate of healthy subjects exhibits complex variability that is not well understood. While heart rate variability is partly effected by autonomic nervous system modulation, cardiac pacemaker cells exhibit their own intrinsic variability in spontaneous action potential (AP) cycle length (CL) [2]. The present dogma is that intrinsic CL variability of cardiac pacemaker cells (i.e. single, isolated cells) is caused by stochastic opening/closing of membrane ion channels [2,3]. The paradigm of cardiac pacemaker cell function, has recently shifted from a mainly electrophysiological description to a coupled system of two oscillators (or ‘‘clocks’’) involving a voltage-dependent membrane clock, and an intracellular Ca2+. In the absence of APs, the SR in cardiac ventricular cells generates spontaneous, stochastic local Ca2+ releases (dubbed ‘‘Ca2+ sparks’’) via ryanodine receptors
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