title: Heart Rate Acceleration of a Subsidiary Pacemaker by β-Adrenergic Stimulation.
abstract: OBJECTIVE
  Recent evidence indicates that the membrane voltage and Ca(2+) clocks jointly regulate sinoatrial node (SAN) automaticity. However, the mechanism of heart rhythm acceleration of the subsidiary pacemaker (SP) during β-adrenergic stimulation is still unknown. Here we tested the hypothesis that the heart rate acceleration of the SP by β-adrenergic stimulation involves synergistic interactions between both clock mechanisms.
  
  
  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 µmol/L isoproterenol infusion increased the heart rate from 82±9 to 166±18 bpm (102%) with late diastolic Ca(i) 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 µmol/L, n=3), whereas, it was suppressed to 69±7 bpm (24% from baseline) by sarcoplasmic reticulum (SR) Ca(2+) emptying with administering ryanodine (10 µmol/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 Ca(2+) emptying (n=3).
  
  
  CONCLUSIONS
  Acceleration of the Ca(2+) clock in the SP plays an important role in the heart rate acceleration during β-adrenergic stimulation, and this interacts synergistically with the voltage clock to increase the heart rate.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sanghoon
authors.initials: S
authors.lastname: Park
authors.forename: Hyerim
authors.initials: H
authors.lastname: Park
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Hwang
authors.forename: Jaemin
authors.initials: J
authors.lastname: Shim
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Sung
authors.forename: Jong-Youn
authors.initials: JY
authors.lastname: Kim
authors.forename: Hui-Nam
authors.initials: HN
authors.lastname: Pak
authors.forename: Moon-Hyoung
authors.initials: MH
authors.lastname: Lee
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joung