Mary S. Kim, Oliver Monfredi, Larissa A. Maltseva, Edward G. Lakatta, and Victor A. Maltsev*


Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD 21224, USA; [email protected] (M.S.K.); [email protected] (O.M.); [email protected] (L.A.M.); [email protected] (E.G.L.)


Calcium Imaging, Cell Biology


The heartbeat is initiated by pacemaker cells residing in the sinoatrial node (SAN). SAN cells generate spontaneous action potentials (APs), i.e., normal automaticity. The sympathetic nervous system increases the heart rate commensurate with the cardiac output demand via stimulation of SAN β-adrenergic receptors (βAR). While SAN cells reportedly represent a highly heterogeneous cell population, the current dogma is that, in response to βAR stimulation, all cells increase their spontaneous AP firing rate in a similar fashion. The aim of the present study was to investigate the cell-to-cell variability in the responses of a large population of SAN cells. We measured the βAR responses among 166 single SAN cells isolated from 33 guinea pig hearts. In contrast to the current dogma, the SAN cell responses to βAR stimulation substantially varied. In each cell, changes in the AP cycle length were highly correlated (R2 = 0.97) with the AP cycle length before βAR stimulation. While, as expected, on average, the cells increased their pacemaker rate, greater responses were observed in cells with slower basal rates, and vice versa: cells with higher basal rates showed smaller responses, no responses, or even decreased their rate. Thus, βAR stimulation synchronized the operation of the SAN cell population toward a higher average rate, rather than uniformly shifting the rate in each cell, creating a new paradigm of βAR-driven fight-or-flight responses among individual pacemaker cells.



The camera was mounted on a Zeiss Axiovert 100 inverted microscope (Carl Zeiss, Inc., Germany) with a ×63 oil immersion lens and a fluorescence excitation light source CoolLED pE-300-W (CoolLED Ltd. Andover, UK).

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The pE-300white is a popular illuminator for everyday fluorescent screening and analysis with simple operatation and individual irradiance control of each LED channel.

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