Heart Rate Acceleration of a Subsidiary Pacemaker by beta-Adrenergic Stimulation

ABSTRACT

BACKGROUND AND OBJECTIVES: Recent evidence indicates that the membrane voltage and Ca2+ clocks jointly regulate sinoatrial node (SAN) automaticity. However, the mechanism of heart rhythm acceleration of the subsidiary pacemaker (SP) during beta-adrenergic stimulation is still unknown. Here we tested the hypothesis that the heart rate acceleration of the SP by beta-adrenergic stimulation involves synergistic interactions between both clock mechanisms. SUBJECTS AND METHODS: We performed optical mapping and pharmacological interventions in 15 isolated Langendorff-perfused canine right atriums (RA). The SP model was produced by ligation of the SAN artery at the mid portion of the sulcus terminalis. RESULTS: In the 6 RAs with an intact SAN, 1 micromol/L isoproterenol infusion increased the heart rate from 82+/-9 to 166+/-18 bpm (102%) with late diastolic Cai elevation (LDCAE) at the superior SAN. However, in the 6 SP models, the heart rate increased from 55+/-10 bpm to 106+/-11 bpm (92%, p=0.005) without LDCAE at the earliest activation site. The isoproterenol induced heart rate increase was reversed to 74+/-5 bpm (33% from baseline) by administering an infusion of the funny current blocker ZD 7288 (3 micromol/L, n=3), whereas, it was suppressed to 69+/-7 bpm (24% from baseline) by sarcoplasmic reticulum (SR) Ca2+ emptying with administering ryanodine (10 micromol/L) plus thapsigargin (200 nmol/L, n=3). The isoproterenol induced heart rate increase was completely abolished by combined treatment with funny current blocker and SR Ca2+ emptying (n=3). CONCLUSION: Acceleration of the Ca2+ clock in the SP plays an important role in the heart rate acceleration during beta-adrenergic stimulation, and this interacts synergistically with the voltage clock to increase the heart rate.