Intracellular Calcium Dynamics and Acceleration of Sinus Rhythm by β-Adrenergic Stimulation

Background— Recent evidence indicates that membrane voltage and Ca2+ clocks jointly regulate sinoatrial node (SAN) automaticity. Here we test the hypothesis that sinus rate acceleration by β-adrenergic stimulation involves synergistic interactions between these clock mechanisms. Methods and Results— We simultaneously mapped intracellular calcium (Cai) and membrane potential in 25 isolated canine right atrium, using previously described criteria of the timing of late diastolic Cai elevation (LDCAE) relative to the action potential upstroke to detect the Ca2+ clock. Before isoproterenol, the earliest pacemaking site occurred in the inferior SAN, and LDCAE was observed in only 4 of 25 preparations. Isoproterenol infusion (1 μmol/L) increased sinus rate and shifted pacemaking site to superior SAN, concomitant with the appearance of LDCAE preceding the action potential upstroke by 98±31 ms. Caffeine had similar effects, whereas sarcoplasmic reticulum Ca2+ depletion with ryanodine and thapsigargin prevented iso...