Background - Recent evidence indicates that membrane voltage and Ca 2+ 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 (Ca 1) and membrane potential in 25 isolated canine right atrium, using previously described criteria of the timing of late diastolic Ca1 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 isoproterenol-induced LDCAE and blunted sinus rate acceleration. Ca1 transient relaxation time during isoproterenol was shorter in superior SAN (124±34 ms) than inferior SAN (138±24 ms; P=0.01) or right atrium (164±33 ms; P=0.001) and was associated with a lower sarcoplasmic reticulum Ca2+ ATPase pump to phospholamban protein ratio in SAN than in right atrium. Hyperpolarization- activated pacemaker current (If) blockade with ZD 7288 modestly blunted but did not prevent LDCAE or sinus rate acceleration by isoproterenol. Conclusions - Acceleration of the Ca2+ clock in the superior SAN plays an important role in sinus acceleration during β-adrenergic stimulation, interacting synergistically with the voltage clock to increase sinus rate.
All Science Journal Classification (ASJC) codes
- Cardiology and Cardiovascular Medicine
- Physiology (medical)