Electrophysiological heterogeneity of pacemaker cells in the rabbit intercaval region, including the SA node: insights from recording multiple ion currents in each cell

Abstract

Cardiac pacemaker cells, including cells of the sinoatrial node, are heterogeneous in size, morphology, and electrophysiological characteristics. The exact extent to which these cells differ electrophysiologically is unclear yet is critical to understanding their functioning. We examined major ionic currents in individual intercaval pacemaker cells (IPCs) sampled from the paracristal, intercaval region (including the sinoatrial node) that were spontaneously beating after enzymatic isolation from rabbit hearts. The beating rate was measured at baseline and after inhibition of the Ca²⁺ pump with cyclopiazonic acid. Thereafter, in each cell, we consecutively measured the density of funny current ( I_f), delayed rectifier K⁺ current ( I_K) (a surrogate of repolarization capacity), and L-type Ca²⁺ current ( I_Ca,L) using whole cell patch clamp_. The ionic current densities varied to a greater extent than previously appreciated, with some IPCs demonstrating very small or zero I_f . The density of none of the currents was correlated with cell size, while I_Ca,L and I_f densities were related to baseline beating rates. I_f density was correlated with I_K density but not with that of I_Ca,L. Inhibition of Ca²⁺ cycling had a greater beating rate slowing effect in IPCs with lower I_f densities. Our numerical model simulation indicated that 1) IPCs with small (or zero) I_f or small I_Ca,L can operate via a major contribution of Ca²⁺ clock, 2) I_f-Ca²⁺-clock interplay could be important for robust pacemaking function, and 3) coupled I_f- I_K function could regulate maximum diastolic potential. Thus, we have demonstrated marked electrophysiological heterogeneity of IPCs. This heterogeneity is manifested in basal beating rate and response to interference of Ca²⁺ cycling, which is linked to I_f. NEW & NOTEWORTHY In the present study, a hitherto unrecognized range of heterogeneity of ion currents in pacemaker cells from the intercaval region is demonstrated. Relationships between basal beating rate and L-type Ca²⁺ current and funny current ( I_f) density are uncovered, along with a positive relationship between I_f and delayed rectifier K⁺ current. Links are shown between the response to Ca²⁺ cycling blockade and I_f density.

Keywords: calcium; heterogeneity; ion channels; sarcoplasmic reticulum; sinoatrial node cell.