Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker cells

Abstract

1 The cellular mechanisms governing cardiac atrial pacemaker activity are not clear. In the present study we used perforated patch voltage clamp and confocal fluorescence microscopy to study the contribution of intracellular Ca²⁺ release to automaticity of pacemaker cells isolated from cat right atrium. 2 In spontaneously beating pacemaker cells, an increase in subsarcolemmal intracellular Ca²⁺ concentration occurred concomitantly with the last third of diastolic depolarization due to local release of Ca²⁺ from the sarcoplasmic reticulum (SR), i.e. Ca²⁺ sparks. Nickel (Ni²⁺; 25–50 μM), a blocker of low voltage-activated T-type Ca²⁺ current ((I_Ca,T), decreased diastolic depolarization, prolonged pacemaker cycle length and suppressed diastolic Ca²⁺ release. 3 Voltage clamp analysis indicated that the diastolic Ca²⁺ release was voltage dependent and triggered at about -60 mV. Ni²⁺ suppressed low voltage-activated Ca²⁺ release. Moreover, low voltage-activated Ca²⁺ release was paralleled by a slow inward current presumably due to stimulation of Na⁺-Ca²⁺ exchange (I_Na-Ca). Low voltage-activated Ca²⁺ release was found in both sino-atrial node and latent atrial pacemaker cells but not in working atrial myocytes. 4 These findings suggest that low voltage-activated I_Ca,T triggers subsarcolemmal Ca²⁺ sparks, which in turn stimulate I_Na-Ca to depolarize the pacemaker potential to threshold. This novel mechanism indicates a pivotal role for I_Ca,T and subsarcolemmal intracellular Ca²⁺ release in normal atrial pacemaker activity and may contribute to the development of ectopic atrial arrhythmias.