The role of Ca²⁺ release from sarcoplasmic reticulum in the regulation of sinoatrial node automaticity

The role of Ca²⁺ release channels in the sarcoplasmic reticulum in modulating physiological automaticity of the sinoatrial (SA) node was studied by recording transmembrane action potentials and membrane ionic currents in small preparations of the rabbit SA node. Ryanodine, which modifies the conductance and gating behavior of the Ca²⁺ release channels, was used to block Ca²⁺ release from the sarcoplasmic reticulum. Superfusion of 1-mM ryanodine decreased the spontaneous firing frequency as well as the maximal rate of depolarization of the SA, and these reductions reached a steady state within approximately 5 min. The action potential recordings revealed that the latter part of diastolic depolarization was depressed and that the take-off potential became less negative. This suggested that the negative chronotropic effect of ryanodine resulted from the blockade of physiological Ca²⁺ release from the sarcoplasmic reticulum. In voltage clamp experiments, using double-microelectrode techniques, ryanodine did not markedly reduce the Ca²⁺ current (I_Ca) but decreased the delayed rectifying K+ current (I_K), the steady-state inward current (I_ss), and the hyperpolarization-activated inward current (I_h). These observations suggest, that, even when the function of Ca²⁺ channels in the cell membrane is normally maintained, depression of Ca²⁺ release channels in the sarcoplasmic reticulum would prevent sufficient elevation of the Ca²⁺ concentration in SA node cells for the activation of various ionic currents, and, thus adversely affect the physiological automaticity of this primary cardiac pacemaker.