Electrical excitation of the mammalian heart originates from specialized pacemaker cells located in specific regions of the right atrium. The right atrium contains both primary (SA node) and latent pacemaker cells. Latent atrial pacemakers are specialized cells located outside of the SA node in specific regions of the inferior right atrium. In the event of SA node failure, latent atrial pacemaker activity can assume pacemaker control of atrial function and may generate atrial arrhythmias. In general, the electrical activity of cardiac pacemakers is determined by multiple mechanisms primarily dependent on ion channel currents within the plasma membrane. However, interventions that alter Ca²⁺ release from the sarcoplasmic reticulum (SR), alter pacemaker activity and therefore suggest a role for intracellular Ca²⁺ release in atrial pacemaker activity (Rubenstein & Lipsius, 1989; Rigg & Terrar, 1996). Therefore, the following experiments investigated the mechanisms by which intracellular Ca²⁺ release contributes to atrial pacemaker function.

Adult cats were anaesthetised with sodium pentobarbital (70 mg kg^-1, I.P.). Atrial pacemaker cells were isolated by Langendorff perfusion and collagenase treatment. Inhibition of intracellular SR Ca²⁺ release by ryanodine specifically depresses the last third of diastolic depolarization and markedly prolongs pacemaker cycle length (Rubenstein & Lipsius, 1989). Moreover, in spontaneously beating pacemaker cells, clamping the membrane voltage during the last third of diastolic depolarization elicits a slowly developing inward current, identified as Na-Ca exchange current (Zhou & Lipsius, 1993). Inhibition of SR Ca²⁺ release by ryanodine concomitantly inhibits the Na-Ca exchange current, diastolic depolarization and pacemaker rate. Confocal fluorescent microscopy reveals an increase in subsarcolemmal intracellular Ca²⁺ concentration due to local SR Ca²⁺ release, i.e. Ca²⁺ sparks during diastolic depolarization (Hüser et al. 2000). Voltage-clamp ramps within the pacemaker voltage range indicate that the diastolic Ca²⁺ release was voltage dependent and triggered at about -60 mV, a voltage too negative for activation of L-type Ca²⁺ current but compatible with activation of T-type Ca²⁺ current. In free-running pacemaker cells, nickel (Ni²⁺; 25-50 mM), a blocker of low voltage-activated T-type Ca²⁺ current, decreases diastolic depolarization, prolongs pacemaker cycle length and suppresses diastolic Ca²⁺ release. Ni²⁺ also suppresses low-voltage-activated Ca²⁺ release elicited by voltage-clamp ramps. Low-voltage-activated Ca²⁺ release was paralleled by a slow inward current presumably due to stimulation of Na-Ca exchange. Low-voltage-activated Ca²⁺ release was more prominent in latent atrial pacemaker cells than in SA node pacemaker cells and absent in working atrial myocytes. Gross morphology of latent atrial and SA node pacemaker cells are similar. However, latent atrial pacemaker cells exhibit a unique architecture of subsarcolemmal cisternae not seen in SA node pacemaker cells. In adjacent latent atrial pacemaker cells, subsarcolemmal cisternae are prominent in size and directly apposed to one another along the adjacent surface membranes.

We conclude that low-voltage-activated T-type Ca²⁺ current triggers subsarcolemmal Ca²⁺ sparks, which in turn, stimulates Na-Ca exchange current to depolarize the pacemaker potential towards threshold. The role of intracellular Ca²⁺ release may be more prominent in latent than SA node pacemaker activity. This mechanism therefore contributes to normal pacemaker function and may underlie atrial arrhythmias that are promoted by alterations in intracellular Ca²⁺ metabolism.

The animal procedures using in this study were in accordance with the guidelines of the Animal Care and Use Committee of Loyola University Medical Center.