Abstract 2663: Mechanisms of Automaticity of the Atrial Ectopic Pacemaker
Background Recent evidence indicates that spontaneous sarcoplasmic reticulum (SR) Ca release underlies the mechanism of sinoatrial node (SAN) acceleration during beta stimulation, indicating the importance of Ca clock in SAN automaticity. Whether or not the same mechanism applies to atrial ectopic pacemakers (AEP) remains unclear.
Methods We simultaneously mapped intracellular calcium (Cai) and membrane potential (Vm) in 13 isolated canine right atria. The timing of late diastolic Cai elevation (LDCAE) relative to the action potential (AP) upstroke was used to detect the Ca clock activity. The amplitude of Cai of a paced beat was defined as 1 arbitrary unit (AU). Isoproterenol (ISO), ryanodine, dantrolene and ZD7288 were given after baseline recordings.
Results ISO augmented LDCAE in SAN (1.38±0.23 to 3.72±0.58 AU, P=0.015), induced a superior shift of the pacemaking site and dose-dependently increased the sinus rate by 67.6±8.8 % at 1.0 μM of ISO (P=0.002). Ryanodine (3 μmol/L), which inhibits SR Ca release, reduced LDCAE in SAN from 1.38±0.23 to 0.20±0.04 AU (P=0.004), resulting in an inferior shift of the pacemaking site. Sinus rate decreased significantly in a dose-dependent fashion (−19.8±5.8 % at ryanodine 3.0 μM, P=0.043). At 10 μM, ryanodine completely inhibited SAN automaticity. However, the AEP from lower crista terminalis was resistant to ryanodine and became the dominant pacemaker, activating at 79±5 bpm (p=0.034 compared with baseline sinus rate of 104±9 bpm). Dantrolene, a type 1 ryanodine receptor (RyR) blocker, did not influence sinus node function (sinus rate 95±11 bpm with 100 μM of dantrolene, N=4, P=0.890). There was no change of the leading pacemaker site during dantrolene infusion. The If current blocker, ZD7288 (30 μmol/L), inhibited AEP, resulting in profound bradycardia at 25±9 bpm.
Conclusions - These findings provide further evidence that ISO-induced increase of superior SAN activity involves spontaneous Ca release from type 2 RyR. As compared with SAN, the AEP is less dependent on the Ca clock and more dependent on the membrane clock for its automaticity. Therefore, AEP can effectively serve as a backup pacemaker when the Ca clock is inhibited.