Fig. 3.

A: simulations showing the novel mechanism of β-AR stimulation to integrate the function of system components. While the major immediate mechanism of cycle length reduction is an earlier and stronger I_NCX, the stronger and more frequent I_CaL critically supports this I_NCX function by supplying more Ca²⁺ to the cell and thereby enhancing SR function. Simulated traces are synchronized at the phase of membrane potential (V_m) = 0 (vertical dashed line) to show the earlier and stronger activation of diastolic Ca²⁺ release (j_SRCarel) and I_NCX, resulting in the earlier and stronger diastolic depolarization(DD) acceleration. B: an example experiment, in which submembrane Ca²⁺ signals by confocal microscopy and V_m by perforated patch clamp were recorded in rabbit sinoatrial node cells (SANCs) in control and after stimulation of β-AR with ISO. Diastolic local Ca²⁺ releases (LCRs) are shown by yellow arrows. ISO increases the LCR signal mass and shifts the LCR occurrence to earlier times within the spontaneous cycle. Red curves (below the confocal images) show the time course of spatial averages calculated within the location marked by double-headed arrows along the scanning lines. This important effect is predicted by our model (see the Ca²⁺ release flux in A, solid vertical arrow). [Images and time series in B were reproduced for illustration from Vinogradova et al. (49) and modified by adding LCR labels and the arrows showing the LCR periods, respectively.]