Introduction: Recent evidence indicates that membrane voltage and Ca2+ clocks jointly regulate sinoatrial node (SAN) automaticity. However, the mechanism of heart rhythm acceleration of subsidiary pacemaker (SP) during 棺-adrenergic stimulation is still unknown. Here we test the hypothesis that heart rate acceleration of subsidiary pacemaker (SP) by 棺-adrenergic stimulation involves synergistic interactions between these clock mechanisms.
Methods: We performed optical mapping and pharmacological interventions in 15 isolated Langendorff-perfused canine right atriums (RA). Subsidiary SP model were produced by ligation of SAN artery at the mid portion of sulcus terminalis.
Results: In 6 RAs with intact SAN, isoproterenol infusion of 1 µmol/L increased heart rate from 82 짹 9 to 166 짹 18 bpm (102%) with late diastolic Cai elevation (LDCAE) at superior SAN. In 6 SP models, heart rate increased from 55 짹 10 bpm to 106 짹 11 bpm (92%, p=0.005). However, we could not find LDCAE in the SP model at baseline and even during isoproterenol infusion. The isoproterenol induced heart rate increase was reversed to 74 짹 5 bpm (33% from baseline) by funny current blocker, ZD 7288 infusion (3 關mol/L, n=3). Whereas, it was suppressed to 69 짹 7 bpm (24% from baseline) by SR Ca2+ emptying with ryanodine (10 µmol/L) plus thapsigargin (200 nmol/L, n=3). The isoproterenol induced heart rate increase was further decreased to 44 짹 10 bpm (-20% from baseline) by combined infusion of ryanodine (10 µmol/L), thapsigargin (200 nmol/L) and ZD 7288 (3 µmol/L) (n=3).
Conclusion: Acceleration of the Ca2+ clock in SP plays an important role in heart rate acceleration during 棺-adrenergic stimulation, interacting synergistically with the voltage clock to increase heart rate.