title: Intracellular calcium dynamics and acceleration of sinus rhythm by beta-adrenergic stimulation.
abstract: 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 beta-adrenergic stimulation involves synergistic interactions between these clock mechanisms.
  
  
  RESULTS
  We simultaneously mapped intracellular calcium (Ca(i)) and membrane potential in 25 isolated canine right atrium, using previously described criteria of the timing of late diastolic Ca(i) 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 micromol/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. Ca(i) 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 (I(f)) 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 beta-adrenergic stimulation, interacting synergistically with the voltage clock to increase sinus rate.
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Boyoung
authors.initials: B
authors.lastname: Joung
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.forename: Seongwook
authors.initials: S
authors.lastname: Han
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Chen
authors.forename: Marcelle
authors.initials: M
authors.lastname: Stucky
authors.forename: Larry R
authors.initials: LR
authors.lastname: Jones
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
mesh_terms: D000200:Action Potentials; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001683:Biological Clocks; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling; D004285:Dogs; D006325:Heart Atria; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials; D009200:Myocardial Contraction / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D007545:Isoproterenol; D002118:Calcium